PMID- 15322253
OWN - NLM
STAT- in-process
DA  - 20040823
IS  - 0026-895X
VI  - 66
IP  - 3
DP  - 2004 Sep
TI  - Berberine inhibits HIF-1alpha expression via enhanced proteolysis.
PG  - 612-9
AB  - We have studied the antiangiogenic property of berberine. We showed that
      berberine could directly inhibit in vitro human umbilical vein endothelial
      cell (HUVEC) tube formation and migration. In addition, to determine
      whether berberine could influence the cross-talk between the gastric
      adenocarcinoma cell line SC-M1 and vascular endothelial cells, we
      performed modified confrontation culture experiments and showed that
      berberine (7.5 microM, 16 h) could inhibit the capacity of hypoxic SC-M1
      cells to stimulate HUVEC migration. These results demonstrated berberine's
      antiangiogenic property and its clinical potential as an inhibitor of
      tumor angiogenesis. Parallel Western blot analyses revealed that berberine
      prevented hypoxic SC-M1 cultures from expressing vascular endothelial
      growth factor (VEGF) and hypoxia-inducible factor (HIF)-1alpha, two key
      factors in mediating tumor angiogenesis. However, overexpression of
      HIF-1alpha in SC-M1 cells dramatically reversed the inhibitory effect of
      berberine on SC-M1-induced in vitro HUVEC migration. These data indicated
      that HIF-1alpha repression is a critical step in the inhibitory effect of
      berberine on tumor-induced angiogenesis. Northern blot analyses plus
      pulse-chase assays revealed that berberine did not down-regulate
      HIF-1alpha mRNA but destabilized HIF-1alpha protein. We found that
      berberine-induced HIF-1alpha degradation was blocked by a 26S proteasome
      inhibitor. Moreover, immunoprecipitation and Western blot analyses showed
      that berberine increased the lysine-acetylated HIF-1alpha in hypoxic SC-M1
      cultures. These data indicated that a proteasomal proteolytic pathway and
      lysine acetylation were involved in berberine-triggered HIF-1alpha
      degradation. In conclusion, our data provided molecular evidence to
      support berberine as a potent antiangiogenic agent in cancer therapy.
AD  - Department of Medical Education and Research, Shin Kong Wu Ho-Su Memorial
      Hospital, 95 Wen Chang Road, Shih Lin, Taipei 111, Taiwan, Republic of
      China.
FAU - Lin, Shankung
AU  - Lin S
FAU - Tsai, Shiow-Chwen
AU  - Tsai SC
FAU - Lee, Chun-Chung
AU  - Lee CC
FAU - Wang, Bao-Wei
AU  - Wang BW
FAU - Liou, Jer-Young
AU  - Liou JY
FAU - Shyu, Kou-Gi
AU  - Shyu KG
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Mol Pharmacol
JID - 0035623
SB  - IM
EDAT- 2004/08/24 05:00
MHDA- 2004/08/24 05:00
AID - 10.1124/mol.66.3. [doi]
AID - 66/3/612 [pii]
PST - ppublish
SO  - Mol Pharmacol 2004 Sep;66(3):612-9.

PMID- 15289340
OWN - NLM
STAT- completed
DA  - 20040803
DCOM- 20040909
IS  - 0008-5472
VI  - 64
IP  - 15
DP  - 2004 Aug 1
TI  - Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic
      cancer.
PG  - 5338-46
AB  - Hypoxic conditions exist within pancreatic adenocarcinoma, yet pancreatic
      cancer cells survive and replicate within this environment. To understand
      the mechanisms involved in pancreatic cancer adaptation to hypoxia, we
      analyzed expression of a regulator of hypoxia-induced cell death,
      Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). We found that
      BNIP3 was down-regulated in nine of nine pancreatic adenocarcinomas
      compared with normal pancreas despite the up-regulation of other
      hypoxia-inducible genes, including glucose transporter-1 and insulin-like
      growth factor-binding protein 3. Also, BNIP3 expression was undetectable
      even after hypoxia treatment in six of seven pancreatic cancer cell lines.
      The BNIP3 promoter, which was remarkably activated by hypoxia, is located
      within a CpG island. The methylation status of CpG dinucleotides within
      the BNIP3 promoter was analyzed after bisulfite treatment by sequencing
      and methylation-specific PCR. Hypermethylation of the BNIP3 promoter was
      observed in all BNIP3-negative pancreatic cancer cell lines and eight of
      10 pancreatic adenocarcinoma samples. Treatment of BNIP3-negative
      pancreatic cancer cell lines with a DNA methylation inhibitor, 5-aza-2'
      deoxycytidine, restored hypoxia-induced BNIP3 expression. BNIP3 expression
      was also restored by introduction of a construct consisting of a
      full-length BNIP3 cDNA regulated by a cloned BNIP3 promoter. Restoration
      of BNIP3 expression rendered the pancreatic cancer cells notably more
      sensitive to hypoxia-induced cell death. In conclusion, down-regulation of
      BNIP3 by CpG methylation likely contributes to resistance to
      hypoxia-induced cell death in pancreatic cancer.
AD  - Department of Molecular and Integrative Physiology, University of
      Michigan, Ann Arbor, MI 48109-0622, USA.
FAU - Okami, Jiro
AU  - Okami J
FAU - Simeone, Diane M
AU  - Simeone DM
FAU - Logsdon, Craig D
AU  - Logsdon CD
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JID - 2984705R
RN  - 0 (BNIP3 protein, human)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 3)
RN  - 0 (Membrane Proteins)
RN  - 0 (Monosaccharide Transport Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (glucose transporter, GLUT11)
RN  - 2353-33-5 (5-aza-2'-deoxycytidine)
RN  - 320-67-2 (Azacitidine)
SB  - IM
MH  - Adenocarcinoma/genetics/metabolism/pathology
MH  - *Apoptosis
MH  - Azacitidine/*analogs & derivatives/pharmacology
MH  - Cell Hypoxia
MH  - Comparative Study
MH  - CpG Islands
MH  - *DNA Methylation
MH  - *Gene Expression Regulation, Neoplastic
MH  - *Gene Silencing
MH  - Human
MH  - Insulin-Like Growth Factor Binding Protein 3/metabolism
MH  - Membrane Proteins/genetics/*metabolism
MH  - Monosaccharide Transport Proteins/metabolism
MH  - Pancreas/metabolism/pathology
MH  - Pancreatic Neoplasms/*genetics/metabolism/pathology
MH  - Promoter Regions (Genetics)/genetics
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Support, Non-U.S. Gov't
MH  - Tumor Cells, Cultured
EDAT- 2004/08/04 05:00
MHDA- 2004/09/10 05:00
AID - 10.1158/0008-5472.CAN-04-0089 [doi]
AID - 64/15/5338 [pii]
PST - ppublish
SO  - Cancer Res 2004 Aug 1;64(15):5338-46.

PMID- 15288294
OWN - NLM
STAT- in-process
DA  - 20040803
IS  - 0959-8049
VI  - 40
IP  - 12
DP  - 2004 Aug
TI  - Expression of hypoxia-inducible factor (HIF)-1alpha is associated with
      vascular endothelial growth factor expression and tumour angiogenesis in
      human oesophageal squamous cell carcinoma.
PG  - 1904-12
AB  - The purpose of this study was to examine the relationship between hypoxia
      inducible factor (HIF)-1alpha expression, vascular endothelial growth
      factor (VEGF) expression, and tumour vascularity in squamous cell
      carcinoma of the oesophagus. Expression of HIF-1alpha and VEGF was
      examined in two oesophageal squamous cell carcinoma cell lines (TE2, TE3)
      and 82 archival surgical specimens of human oesophageal squamous cell
      carcinoma tissue. In both cell lines, the levels of HIF-1alpha protein and
      VEGF mRNA were increased under hypoxic conditions. Thirty-two of the 82
      (39%) tumour specimens showed high levels of HIF-1alpha immunoreactivity
      in the nuclei and/or cytoplasm of cancer cells. HIF-1alpha expression
      correlated significantly with venous invasion, VEGF expression, and
      microvessel density. Among the 47 patients who did not receive
      pre-operative chemotherapy, the outcome of those with high
      HIF-1alpha-expressing tumours was significantly poorer than that of those
      with low HIF-1alpha-expressing tumours. These results suggest that
      HIF-1alpha and VEGF expression are important determinants of survival in
      squamous cell carcinoma of the oesophagus.
AD  - Department of Medicine and Molecular Science, Graduate School of
      Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku,
      Hiroshima 734-8551, Japan.
FAU - Kimura, Shigeru
AU  - Kimura S
FAU - Kitadai, Yasuhiko
AU  - Kitadai Y
FAU - Tanaka, Shinji
AU  - Tanaka S
FAU - Kuwai, Toshio
AU  - Kuwai T
FAU - Hihara, Jun
AU  - Hihara J
FAU - Yoshida, Kazuhiro
AU  - Yoshida K
FAU - Toge, Tetsuya
AU  - Toge T
FAU - Chayama, Kazuaki
AU  - Chayama K
LA  - eng
PT  - Journal Article
PL  - England
TA  - Eur J Cancer
JID - 9005373
SB  - IM
EDAT- 2004/08/04 05:00
MHDA- 2004/08/04 05:00
PHST- 2004/Jan/06 [received]
PHST- 2004/Apr/23 [revised]
PHST- 2004/Apr/29 [accepted]
AID - 10.1016/j.ejca.2004.04.035 [doi]
AID - S095980490400406X [pii]
PST - ppublish
SO  - Eur J Cancer 2004 Aug;40(12):1904-12.

PMID- 15199114
OWN - NLM
STAT- completed
DA  - 20040616
DCOM- 20040624
IS  - 1460-2105
VI  - 96
IP  - 12
DP  - 2004 Jun 16
TI  - Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth,
      angiogenesis, and vessel maturation.
PG  - 946-56
AB  - BACKGROUND: Hypoxia-inducible factor 1 (HIF-1), a heterodimer comprising
      the oxygen-regulated subunit, HIF-1alpha, and HIF-1beta, mediates
      transcription of the gene for vascular endothelial growth factor (VEGF).
      Overexpression of HIF-1alpha is associated with tumor angiogenesis and
      tumor cell proliferation and invasion. We examined the effects of
      inhibiting HIF-1alpha activity on angiogenesis and human gastric cancer
      growth in vivo. METHODS: Human gastric cancer TMK-1 cells were stably
      transfected with pHIF-1alphaDN, an expression plasmid encoding a
      dominant-negative form of HIF-1alpha that dimerizes with endogenous
      HIF-1beta to produce HIF-1 complexes that cannot activate transcription,
      or with the empty expression vector (pCEP4). Two clones of
      pHIF-1alphaDN-transfected cells, DN2 and DN3, were tested in all
      experiments. We used an enzyme-linked immunosorbent assay to measure VEGF
      secretion by transfected cells cultured in hypoxic (1% O2) or nonhypoxic
      (20% O2) conditions. We used subcutaneous and orthotopic mouse tumor
      models to examine the growth of tumors derived from injected
      pHIF-1alphaDN-or pCEP4-transfected cells. Tumor cell proliferation, vessel
      area (a measure of functional vascular volume), and tumor endothelial cell
      association with pericyte-like cells (a measure of vessel maturation) were
      analyzed by immunohistochemical or immunofluorescent staining. All
      statistical tests were two-sided. RESULTS: DN2 cells and DN3 cells
      secreted less VEGF than pCEP4-transfected TMK-1 cells when cultured in
      nonhypoxic or hypoxic conditions (e.g., DN2 versus pCEP4 in nonhypoxic
      conditions: 645 pg of VEGF/10(6) cells versus 1591 pg of VEGF/10(6) cells,
      difference = 946 pg of VEGF/10(6) cells [95% confidence interval [CI] =
      640 to 1251 pg of VEGF/10(6) cells; P =.006]; DN2 versus pCEP4 in hypoxic
      conditions: 785 pg of VEGF/10(6) cells versus 2807 pg of VEGF/10(6) cells,
      difference = 2022 pg of VEGF/10(6) cells [95% CI = 1871 to 2152 pg of
      VEGF/10(6) cells; P<.001]). In the subcutaneous tumor model, tumors
      derived from DN2 or DN3 cells had lower final volumes, weights, and vessel
      areas, less tumor endothelial cell association with desmin-positive cells,
      and fewer proliferating tumor cells than tumors derived from
      pCEP4-transfected cells. In the orthotopic tumor model, tumors derived
      from DN2 cells had smaller volumes and less vessel area and maturation
      than tumors derived from pCEP4-transfected cells. CONCLUSIONS: Inhibition
      of HIF-1alpha activity impairs gastric tumor growth, angiogenesis, and
      vessel maturation.
AD  - Department of Cancer Biology, The University of Texas M. D. Anderson
      Cancer Center, Houston 77030-4009, USA.
FAU - Stoeltzing, Oliver
AU  - Stoeltzing O
FAU - McCarty, Marya F
AU  - McCarty MF
FAU - Wey, Jane S
AU  - Wey JS
FAU - Fan, Fan
AU  - Fan F
FAU - Liu, Wenbiao
AU  - Liu W
FAU - Belcheva, Anna
AU  - Belcheva A
FAU - Bucana, Corazon D
AU  - Bucana CD
FAU - Semenza, Gregg L
AU  - Semenza GL
FAU - Ellis, Lee M
AU  - Ellis LM
LA  - eng
GR  - CA 16672/CA/NCI
GR  - CA74821/CA/NCI
GR  - P50-CA103175/CA/NCI
GR  - T-32 09599/PHS
PT  - Journal Article
PL  - United States
TA  - J Natl Cancer Inst
JID - 7503089
RN  - 0 (HIF1alpha protein)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 138391-32-9 (Arnt protein)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Blotting, Western
MH  - Cell Division
MH  - Cell Line, Tumor
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fluorescent Antibody Technique
MH  - Gene Expression Regulation, Neoplastic
MH  - Human
MH  - Mice
MH  - Mice, Nude
MH  - Mutation
MH  - Neovascularization, Pathologic/genetics/*metabolism/prevention & control
MH  - Random Allocation
MH  - Receptors, Aryl Hydrocarbon/metabolism
MH  - Stomach Neoplasms/*blood supply/genetics/*metabolism
MH  - Support, U.S. Gov't, P.H.S.
MH  - Transcription Factors/antagonists & inhibitors/genetics/*metabolism
MH  - Transcription, Genetic
MH  - Transfection
MH  - Transplantation, Heterologous
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/*genetics
EDAT- 2004/06/17 05:00
MHDA- 2004/06/25 05:00
PST - ppublish
SO  - J Natl Cancer Inst 2004 Jun 16;96(12):946-56.

PMID- 15135470
OWN - NLM
STAT- completed
DA  - 20040511
DCOM- 20040812
IS  - 0748-7983
VI  - 30
IP  - 5
DP  - 2004 Jun
TI  - Hypoxia-inducible factor 1 (HIF-1) in cancer.
PG  - 465-8
AB  - Hypoxia is a common feature of many cancers. It contributes to local and
      systemic tumour progression as well as potentially compromising
      radiotherapy and chemotherapy. Hypoxia-inducible factor 1 (HIF-1) is an
      essential component in changing the transcriptional response of tumours
      under hypoxia. It targets the transcription of over 60 genes involved in
      many aspects of cancer biology including cell survival, glucose
      metabolism, cell invasion and angiogenesis. Over-expression of HIF-1 has
      been associated with increased patient mortality in several cancer types
      including breast, stomach, cervical, endometrial and ovarian cancers. The
      pharmacological manipulation of HIF-1 has marked effects on tumour growth,
      and it could prove to be an important target for drug therapy, both in
      cancer and in other hypoxia-dependent disease states.
AD  - Wolfson Institute for Biomedical Research, The Cruciform Building,
      University College London, London, UK.
FAU - Quintero, M
AU  - Quintero M
FAU - Mackenzie, N
AU  - Mackenzie N
FAU - Brennan, P A
AU  - Brennan PA
LA  - eng
PT  - Journal Article
PT  - Review
PT  - Review, Tutorial
PL  - England
TA  - Eur J Surg Oncol
JID - 8504356
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF-1 protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Cell Hypoxia/genetics
MH  - DNA-Binding Proteins/*genetics
MH  - Human
MH  - Neoplasms/*genetics/metabolism/therapy
MH  - Nuclear Proteins/*genetics
MH  - Transcription Factors/physiology
RF  - 34
EDAT- 2004/05/12 05:00
MHDA- 2004/08/13 05:00
PHST- 2004/Mar/04 [accepted]
AID - 10.1016/j.ejso.2004.03.008 [doi]
AID - S0748798304000666 [pii]
PST - ppublish
SO  - Eur J Surg Oncol 2004 Jun;30(5):465-8.

PMID- 15113858
OWN - NLM
STAT- completed
DA  - 20040428
DCOM- 20040525
IS  - 0021-9746
VI  - 57
IP  - 5
DP  - 2004 May
TI  - Expression of vascular endothelial growth factor, hypoxia inducible factor
      1alpha, and carbonic anhydrase IX in human tumours.
PG  - 504-12
AB  - AIMS: To measure vascular endothelial growth factor (VEGF-A) mRNA in a
      large, diverse cohort of tumours and to investigate whether VEGF-A
      expression is associated with markers of hypoxia, including hypoxia
      inducible factor 1alpha (HIF-1alpha) and carbonic anhydrase IX (CA9).
      METHODS: The expression of VEGF-A and CA9 was assessed in 5067 fresh
      frozen human tissue samples and 238 cell lines by DNA microarray analysis.
      In addition, tissue microarrays were constructed from 388 malignancies to
      investigate the expression of VEGF-A and HIF-1alpha by in situ
      hybridisation and immunohistochemistry, respectively. RESULTS: VEGF-A was
      significantly upregulated in primary malignancies of the breast, cervix,
      colon and rectum, oesophagus, head and neck, kidney, ovary, skin, urinary
      system, and white blood cells by DNA microarray analysis. However, VEGF-A
      expression only correlated with CA9 expression in renal tissues. In the
      tissue microarrays, HIF-1alpha positive cores showed a significant
      increase in VEGF-A expression in lung, ovary, soft tissue, and thyroid
      malignancies. CONCLUSIONS: The expression of VEGF-A is upregulated in a
      large proportion of human malignancies, and may be associated with markers
      of hypoxia. VEGF-A expression can be induced in the absence of hypoxia and
      hypoxia does not always provoke VEGF-A upregulation in tumours.
AD  - Department of Pathology, Genentech Inc, South San Francisco, CA94080, USA.
      adrianj@gene.com
FAU - Jubb, A M
AU  - Jubb AM
FAU - Pham, T Q
AU  - Pham TQ
FAU - Hanby, A M
AU  - Hanby AM
FAU - Frantz, G D
AU  - Frantz GD
FAU - Peale, F V
AU  - Peale FV
FAU - Wu, T D
AU  - Wu TD
FAU - Koeppen, H W
AU  - Koeppen HW
FAU - Hillan, K J
AU  - Hillan KJ
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Clin Pathol
JID - 0376601
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (vascular endothelial growth factor A, human)
RN  - EC 4.2.1.1 (CA9 protein, human)
RN  - EC 4.2.1.1 (Carbonic Anhydrases)
SB  - AIM
SB  - IM
MH  - Antigens, Neoplasm/genetics/metabolism
MH  - Carbonic Anhydrases/genetics/metabolism
MH  - Cell Hypoxia
MH  - DNA, Neoplasm/genetics
MH  - Female
MH  - Human
MH  - Male
MH  - Neoplasm Proteins/genetics/*metabolism
MH  - Neoplasms/*metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - RNA, Messenger/genetics
MH  - RNA, Neoplasm/genetics
MH  - Transcription Factors/genetics/metabolism
MH  - Tumor Cells, Cultured
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/genetics/*metabolism
EDAT- 2004/04/29 05:00
MHDA- 2004/05/27 05:00
PST - ppublish
SO  - J Clin Pathol 2004 May;57(5):504-12.

PMID- 15047156
OWN - NLM
STAT- completed
DA  - 20040329
DCOM- 20040511
IS  - 0006-291X
VI  - 317
IP  - 1
DP  - 2004 Apr 23
TI  - Cysteamine alters redox state, HIF-1alpha transcriptional interactions and
      reduces duodenal mucosal oxygenation: novel insight into the mechanisms of
      duodenal ulceration.
PG  - 121-7
AB  - Our recent studies demonstrated a critical role of enhanced
      transcriptional activity of early growth response factor-1 (Egr-1) in
      early stages of cysteamine-induced duodenal ulcer in rats. Since
      cysteamine is also a reducing agent, the aims of this study were to
      determine the effect of cysteamine on proximal duodenal mucosa: (a) redox
      status, (b) mucosal oxygenation, (c) expression of hypoxia-inducible
      factor 1 (HIF-1alpha) and its binding to DNA, and (d) HIF-1alpha
      interaction with Egr-1 and other redox-sensitive transcription factors.
      Here we demonstrate for the first time that cysteamine treatment reduced
      the duodenal oxygenation by 19% (vs. baseline) and markedly increased the
      redox status in duodenal mucosa (p<0.05). Cysteamine increased HIF-1alpha
      expression, its binding to DNA, and enhanced the HIF-1alpha interactions
      with Egr-1 and other transcription factors (e.g., AP-1, AP-2, L-III BP,
      NF-E1, NF-E2, STAT4, and MRE), their binding to DNA. Thus, these data
      demonstrate the involvement of the redox-dependent regulatory mechanisms
      in the early stages of duodenal ulceration.
AD  - Pathology and Laboratory Medicine Service, Diagnostic and Molecular
      Medicine Health Care Group, Department of Medicine, VA Medical Center, CA
      90822, USA.
FAU - Khomenko, Tetyana
AU  - Khomenko T
FAU - Deng, Xiaoming
AU  - Deng X
FAU - Sandor, Zsuzsanna
AU  - Sandor Z
FAU - Tarnawski, Andrzej S
AU  - Tarnawski AS
FAU - Szabo, Sandor
AU  - Szabo S
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Biochem Biophys Res Commun
JID - 0372516
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Transcription Factors)
RN  - 60-23-1 (Cysteamine)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Animals
MH  - Cell Nucleus/metabolism
MH  - Cysteamine/*pharmacology
MH  - Cytoplasm/metabolism
MH  - DNA/metabolism
MH  - DNA-Binding Proteins/metabolism
MH  - Duodenal Ulcer/*metabolism
MH  - Duodenum/*drug effects/metabolism
MH  - Female
MH  - Intestinal Mucosa/*drug effects/metabolism
MH  - Oxidation-Reduction
MH  - Oxygen Consumption/*drug effects/physiology
MH  - Protein Binding
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Stomach/drug effects/metabolism
MH  - Support, U.S. Gov't, Non-P.H.S.
MH  - Transcription Factors/biosynthesis/*metabolism
MH  - Transcription, Genetic
EDAT- 2004/03/30 05:00
MHDA- 2004/05/12 05:00
PHST- 2004/Mar/04 [received]
AID - 10.1016/j.bbrc.2004.03.017 [doi]
AID - S0006291X04004929 [pii]
PST - ppublish
SO  - Biochem Biophys Res Commun 2004 Apr 23;317(1):121-7.

PMID- 15026543
OWN - NLM
STAT- in-process
DA  - 20040317
IS  - 1535-7163
VI  - 3
IP  - 3
DP  - 2004 Mar
TI  - Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor
      of hypoxia-inducible factor-1alpha.
PG  - 233-44
AB  - The hypoxia-inducible factor-1 (HIF-1) transcription factor is an
      important regulator of tumor response to hypoxia that include increased
      angiogenesis, glycolytic metabolism, and resistance to apoptosis. HIF-1
      activity is regulated by the availability of the HIF-1alpha subunit, the
      levels of which increase under hypoxic conditions. PX-478
      (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid
      N-oxide dihydrochloride) is an inhibitor of constitutive and
      hypoxia-induced HIF-1alpha levels and thus HIF-1 activity. We report that
      PX-478 given to mice suppresses HIF-1alpha levels in HT-29 human colon
      cancer xenografts and inhibits the expression of HIF-1 target genes
      including vascular endothelial growth factor and the glucose
      transporter-1. PX-478 shows antitumor activity against established
      (0.15-0.40 cm(3)) human tumor xenografts with cures of SHP-77 small cell
      lung cancer and log cell kills up to 3.0 for other tumors including HT-29
      colon, PC-3 prostate, DU-145 prostate, MCF-7 breast, Caki-1 renal, and
      Panc-1 pancreatic cancers. Large (0.83 cm(3)) PC-3 prostate tumors showed
      64% regression, which was greater than for smaller tumors. The antitumor
      response to PX-478 was positively correlated with tumor HIF-1alpha levels
      (P < 0.02) and was accompanied by massive apoptosis. The results show that
      PX-478 is an inhibitor of HIF-1alpha and HIF-1 transcription factor
      activity in human tumor xenografts and has marked antitumor activity
      against even large tumor xenografts, which correlates positively with
      HIF-1alpha levels.
AD  - Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
FAU - Welsh, Sarah
AU  - Welsh S
FAU - Williams, Ryan
AU  - Williams R
FAU - Kirkpatrick, Lynn
AU  - Kirkpatrick L
FAU - Paine-Murrieta, Gillian
AU  - Paine-Murrieta G
FAU - Powis, Garth
AU  - Powis G
LA  - eng
GR  - CA52995/CA/NCI
GR  - CA90821/CA/NCI
GR  - CA98920/CA/NCI
PT  - Journal Article
PL  - United States
TA  - Mol Cancer Ther
JID - 101132535
SB  - IM
EDAT- 2004/03/18 05:00
MHDA- 2004/03/18 05:00
PST - ppublish
SO  - Mol Cancer Ther 2004 Mar;3(3):233-44.

PMID- 15024076
OWN - NLM
STAT- completed
DA  - 20040316
DCOM- 20040510
IS  - 0270-7306
VI  - 24
IP  - 7
DP  - 2004 Apr
TI  - Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via
      hypoxia-inducible factor 1-dependent and -independent mechanisms and
      contributes to drug resistance.
PG  - 2875-89
AB  - Solid tumors with disorganized, insufficient blood supply contain hypoxic
      cells that are resistant to radiotherapy and chemotherapy. Drug
      resistance, an obstacle to curative treatment of solid tumors, can occur
      via suppression of apoptosis, a process controlled by pro- and
      antiapoptotic members of the Bcl-2 protein family. Oxygen deprivation of
      human colon cancer cells in vitro provoked decreased mRNA and protein
      levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF-1) was
      dispensable for the down-regulation of Bad but required for that of Bid,
      consistent with the binding of HIF-1alpha to a hypoxia-responsive element
      (positions -8484 to -8475) in the bid promoter. Oxygen deprivation
      resulted in proteosome-independent decreased expression of Bax in vitro,
      consistent with a reduction in global translation efficiency. The
      physiological relevance of Bid and Bax down-regulation was confirmed in
      tumors in vivo. Oxygen deprivation resulted in decreased drug-induced
      apoptosis and clonogenic resistance to agents with different mechanisms of
      action. The contribution of Bid and/or Bax down-regulation to drug
      responsiveness was demonstrated by the relative resistance of normoxic
      cells that had no or reduced expression of Bid and/or Bax and by the
      finding that forced expression of Bid in hypoxic cells resulted in
      increased sensitivity to the topoisomerase II inhibitor etoposide.
AD  - Cellular and Molecular Pharmacology Group, Bioinformatics Group, Paterson
      Institute for Cancer Research, Manchester M20 4BX, United Kingdom.
FAU - Erler, Janine T
AU  - Erler JT
FAU - Cawthorne, Christopher J
AU  - Cawthorne CJ
FAU - Williams, Kaye J
AU  - Williams KJ
FAU - Koritzinsky, Marianne
AU  - Koritzinsky M
FAU - Wouters, Bradley G
AU  - Wouters BG
FAU - Wilson, Clare
AU  - Wilson C
FAU - Miller, Crispin
AU  - Miller C
FAU - Demonacos, Costas
AU  - Demonacos C
FAU - Stratford, Ian J
AU  - Stratford IJ
FAU - Dive, Caroline
AU  - Dive C
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Mol Cell Biol
JID - 8109087
RN  - 0 (BID protein)
RN  - 0 (Bax protein)
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF-1 protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Nucleic Acid Synthesis Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 33419-42-0 (Etoposide)
SB  - IM
MH  - Animals
MH  - Anoxia/*metabolism
MH  - Apoptosis/physiology
MH  - Carrier Proteins/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - DNA-Binding Proteins/*metabolism
MH  - *Down-Regulation
MH  - Drug Resistance, Neoplasm/*physiology
MH  - Etoposide/metabolism
MH  - Female
MH  - Human
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasms/*metabolism/pathology
MH  - Nuclear Proteins/*metabolism
MH  - Nucleic Acid Synthesis Inhibitors/metabolism
MH  - Promoter Regions (Genetics)
MH  - Protein Binding
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Support, Non-U.S. Gov't
MH  - Transplantation, Heterologous
EDAT- 2004/03/17 05:00
MHDA- 2004/05/11 05:00
PST - ppublish
SO  - Mol Cell Biol 2004 Apr;24(7):2875-89.

PMID- 14996738
OWN - NLM
STAT- completed
DA  - 20040303
DCOM- 20040331
IS  - 0008-5472
VI  - 64
IP  - 5
DP  - 2004 Mar 1
TI  - Hypoxia-inducible factor-1-independent regulation of vascular endothelial
      growth factor by hypoxia in colon cancer.
PG  - 1765-72
AB  - The induction of vascular endothelial growth factor (VEGF) is an essential
      feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1)
      transcription factor is known to be a key mediator of this process. In
      colon cancer, the frequently mutated K-ras oncogene also can regulate VEGF
      expression, but the role that K-ras may play in hypoxia is unknown.
      Hypoxia induced VEGF promoter activity, mRNA, and protein levels in colon
      cancer cells. Although HIF-1alpha was induced by hypoxia, VEGF reporter
      constructs with selectively mutated hypoxia-response elements remained
      responsive to hypoxia. In addition, "knockdown" of HIF-1alpha by RNA
      interference only minimally inhibited the hypoxic induction of VEGF. A
      region of the VEGF promoter between -420 and -90 bp mediated this
      HIF-independent induction by hypoxia. The introduction of K-ras(Val12)
      augmented the hypoxic induction of VEGF, and this was observed in
      wild-type and HIF-1alpha knockdown colon cancer cells. Thus, VEGF may be
      induced by hypoxia through HIF-dependent and HIF-independent pathways, and
      K-ras also can induce VEGF in hypoxia independent of HIF-1. These findings
      suggest the existence of multiple mechanisms regulating the hypoxic
      induction of VEGF in colon cancer.
AD  - Gastrointestinal Unit, Department of Medicine, Massachusetts General
      Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
FAU - Mizukami, Yusuke
AU  - Mizukami Y
FAU - Li, Jingnan
AU  - Li J
FAU - Zhang, Xiaobo
AU  - Zhang X
FAU - Zimmer, Michael A
AU  - Zimmer MA
FAU - Iliopoulos, Othon
AU  - Iliopoulos O
FAU - Chung, Daniel C
AU  - Chung DC
LA  - eng
GR  - CA92594/CA/NCI
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JID - 2984705R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF-1 protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - *Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Colonic Neoplasms/*blood supply
MH  - DNA-Binding Proteins/*physiology
MH  - *Gene Expression Regulation, Neoplastic
MH  - Genes, ras
MH  - Human
MH  - Neovascularization, Pathologic/etiology
MH  - Nuclear Proteins/*physiology
MH  - Promoter Regions (Genetics)
MH  - Support, U.S. Gov't, P.H.S.
MH  - Vascular Endothelial Growth Factor A/*genetics
EDAT- 2004/03/05 05:00
MHDA- 2004/04/01 05:00
PST - ppublish
SO  - Cancer Res 2004 Mar 1;64(5):1765-72.

PMID- 14703115
OWN - NLM
STAT- completed
DA  - 20040101
DCOM- 20040806
IS  - 0742-2091
VI  - 19
IP  - 5
DP  - 2003 Oct
TI  - Inhibitory effect of a naphthazarin derivative, S64, on heat shock factor
      (Hsf) activation and glutathione status following hypoxia.
PG  - 273-84
AB  - The presence of hypoxic cells in solid tumors has long been considered a
      problem in cancer treatment. Resistance of hypoxic cells to ionizing
      radiation and anticancer drugs has in part been attributed to changes in
      altered gene expression by hypoxia. We previously reported an activation
      of heat shock factor (Hsf) in murine tumor RIF cells following hypoxia and
      suggested that a subsequent accumulation of heat shock protein(s) (Hsp) is
      likely to contribute to the malignant progression of hypoxic tumor cells
      (Baek et al., 2001). In this study, we showed that hypoxia induced a
      DNA-binding activity of Hsf and activation of hsp70 gene expression in
      colon cancer Clone A cells, and that a naphthazarin derivative, S64,
      significantly inhibited the hypoxia-inducible hsp70 gene expression in
      Clone A cells. We also showed that S64 significantly reduced the cellular
      glutathione levels in this cell line. Considering the proposed effects of
      Hsp and glutathione on radiation and chemotherapy sensitivity, we suggest
      that the inhibitory effects of S64 on Hsf activation and cellular
      glutathione levels have potentially important clinical implications. We
      believe that the previously reported in vitro and in vivo anti-tumor
      effect of S64 (Song et al., 2000a, 2001) might be attributed, at least in
      part, to its effect on Hsf activation and/or glutathione depletion. We
      also believe that the detailed molecular mechanisms underlying the effects
      of S64 on Hsf and glutathione level following hypoxia deserve a more
      rigorous future study, the results of which could offer novel strategy to
      manipulate the resistance mechanisms of solid tumors.
AD  - Division of Chemistry and Biology, University of Incheon, Korea.
      young-mee.park@roswellpark.org
FAU - Park, E M
AU  - Park EM
FAU - Lee, I J
AU  - Lee IJ
FAU - Kim, S H
AU  - Kim SH
FAU - Song, G Y
AU  - Song GY
FAU - Park, Y M
AU  - Park YM
LA  - eng
PT  - Journal Article
PL  - Netherlands
TA  - Cell Biol Toxicol
JID - 8506639
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Heat-Shock Proteins 70)
RN  - 0 (Naphthoquinones)
RN  - 0 (Reactive Oxygen Species)
RN  - 475-38-7 (naphthazarin)
RN  - 63231-63-0 (RNA)
RN  - 6956-96-3 (2,3-dimethoxy-1,4-naphthoquinone)
RN  - 70-18-8 (Glutathione)
RN  - 9007-49-2 (DNA)
RN  - EC 6.3.2.2 (Glutamate-Cysteine Ligase)
SB  - IM
MH  - Animals
MH  - Anoxia
MH  - Antineoplastic Agents/*pharmacology
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Nucleus/metabolism
MH  - DNA/chemistry/metabolism
MH  - Glutamate-Cysteine Ligase/metabolism
MH  - Glutathione/*metabolism
MH  - Heat-Shock Proteins 70/*metabolism
MH  - Mice
MH  - Naphthoquinones/chemistry/*pharmacology
MH  - Protein Binding
MH  - RNA/chemistry
MH  - Reactive Oxygen Species
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Support, Non-U.S. Gov't
MH  - Time Factors
EDAT- 2004/01/02 05:00
MHDA- 2004/08/07 05:00
PST - ppublish
SO  - Cell Biol Toxicol 2003 Oct;19(5):273-84.

PMID- 14695194
OWN - NLM
STAT- completed
DA  - 20031225
DCOM- 20040311
LR  - 20040318
IS  - 0008-5472
VI  - 63
IP  - 24
DP  - 2003 Dec 15
TI  - Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia
      inducible factor-1alpha activation and inhibits tumor growth.
PG  - 8777-83
AB  - Hypoxic stress is one of the major selective pressures in the
      microenvironment of solid tumors, and overcoming this restriction is
      essential for tumor progression. One of the key factors driving the
      cellular response to lack of oxygen is hypoxia inducible factor (HIF), a
      key transcriptional factor. The level of the alpha subunit of HIF-1 is
      regulated by rapid degradation that is controlled by a family of prolyl
      hydroxylases (PHDs/EGLNs), the activity of which depends on oxygen
      availability. Our study shows that ectopic expression of mPHD1 suppressed
      accumulation of HIF-1alpha and secretion of Vascular Endothelial Growth
      Factor after treatment of cells with a hypoxia-mimetic drug. Furthermore,
      when colon carcinoma cells expressing mPHD1 were injected into nude mice,
      tumor growth was inhibited, and the inhibition of tumor growth was
      correlated with increased necrosis and a striking decrease in microvessel
      density. These data demonstrate that inhibition of hypoxia-induced
      activation of HIF-1alpha through activation of HIF-hydroxylase can provide
      a novel therapeutic strategy for inhibition of tumor growth and
      neovascularization and support the development of gene transfer approaches
      based on the activation of HIF-prolyl hydroxylases.
AD  - Departments of Molecular Cell Biology and. Experimental Animals, The
      Weizmann Institute of Science, Rehovot, Israel.
      varda.rotter@weizmann.ac.il
FAU - Erez, Neta
AU  - Erez N
FAU - Milyavsky, Michael
AU  - Milyavsky M
FAU - Eilam, Raya
AU  - Eilam R
FAU - Shats, Igor
AU  - Shats I
FAU - Goldfinger, Naomi
AU  - Goldfinger N
FAU - Rotter, Varda
AU  - Rotter V
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JID - 2984705R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1alpha protein)
RN  - 0 (PHD1 protein, S cerevisiae)
RN  - 0 (Transcription Factors)
RN  - 70-51-9 (Deferoxamine)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
SB  - IM
MH  - Animals
MH  - Cell Division/physiology
MH  - Cell Hypoxia
MH  - DNA-Binding Proteins/biosynthesis/genetics/*physiology
MH  - Deferoxamine/pharmacology
MH  - HCT116 Cells
MH  - Human
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - Neoplasms, Experimental/blood supply/metabolism/*pathology
MH  - Procollagen-Proline Dioxygenase/biosynthesis/genetics/*physiology
MH  - Support, Non-U.S. Gov't
MH  - Trans-Activation (Genetics)/physiology
MH  - Transcription Factors/*antagonists & inhibitors/physiology
MH  - Transplantation, Heterologous
EDAT- 2003/12/26 05:00
MHDA- 2004/03/12 05:00
PST - ppublish
SO  - Cancer Res 2003 Dec 15;63(24):8777-83.

PMID- 14627339
OWN - NLM
STAT- completed
DA  - 20031120
DCOM- 20031203
IS  - 0163-2116
VI  - 48
IP  - 10
DP  - 2003 Oct
TI  - Esophagogastric varices due to arterioportal shunt in a serous cystadenoma
      of the pancreas in von Hippel-Lindau disease.
PG  - 1948-54
AB  - Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited
      disorder characterized by extensively vascularized tumors and cysts in
      specific organs. Angiogenesis is a striking future of VHL disease with its
      characteristic cysts and well-vascularized tumors. The hypervascular
      nature of VHL lesions has been linked to the overproduciton of vascular
      endothelial growth factor (VEGF) through increased expression of hypoxia
      inducible factor-1alpha (HIF-1alpha). Here we describe a rare case of VHL
      disease with esophageal and gastric varices due to arterioportal shunt in
      a serous cystadenoma of the pancreas, which, upon immunohistochemical
      examination, exhibited HIF-1alpha and VEGF expression. Rupture of
      esophageal varices was successfully treated with endoscopic injection
      sclerotherapy.
AD  - Department of Gastroenterology, Osaka City University Medical School,
      Osaka, Japan.
FAU - Okuyama, Masatsugu
AU  - Okuyama M
FAU - Fujiwara, Yasuhiro
AU  - Fujiwara Y
FAU - Hayakawa, Tsuyoshi
AU  - Hayakawa T
FAU - Shiba, Masatsugu
AU  - Shiba M
FAU - Watanabe, Toshio
AU  - Watanabe T
FAU - Tominaga, Kazunari
AU  - Tominaga K
FAU - Tamori, Akihiro
AU  - Tamori A
FAU - Oshitani, Nobuhide
AU  - Oshitani N
FAU - Higuchi, Kazuhide
AU  - Higuchi K
FAU - Matsumoto, Takayuki
AU  - Matsumoto T
FAU - Nakamura, Kenji
AU  - Nakamura K
FAU - Wakasa, Kenichi
AU  - Wakasa K
FAU - Hirohashi, Kazuhiro
AU  - Hirohashi K
FAU - Ashida, Shingo
AU  - Ashida S
FAU - Shuin, Taro
AU  - Shuin T
FAU - Arakawa, Tetsuo
AU  - Arakawa T
LA  - eng
PT  - Case Reports
PT  - Journal Article
PL  - United States
TA  - Dig Dis Sci
JID - 7902782
RN  - 0 (HIF1alpha protein)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - AIM
SB  - IM
MH  - Angiography
MH  - Arteries
MH  - Arteriovenous Fistula/*complications
MH  - Colon/*blood supply
MH  - Cystadenoma, Serous/*blood supply/etiology/metabolism/radiography
MH  - Endoscopy, Digestive System
MH  - Esophageal and Gastric Varices/diagnosis/*etiology/pathology/therapy
MH  - Hippel-Lindau Disease/*complications
MH  - Human
MH  - Immunohistochemistry
MH  - Male
MH  - Middle Aged
MH  - Pancreatic Neoplasms/*blood supply/etiology/metabolism/radiography
MH  - *Portal Vein
MH  - Rupture, Spontaneous/therapy
MH  - Sclerotherapy
MH  - Tomography, X-Ray Computed
MH  - Transcription Factors/metabolism
MH  - Vascular Endothelial Growth Factor A/metabolism
EDAT- 2003/11/25 05:00
MHDA- 2003/12/04 05:00
PST - ppublish
SO  - Dig Dis Sci 2003 Oct;48(10):1948-54.

PMID- 14519649
OWN - NLM
STAT- completed
DA  - 20031001
DCOM- 20040817
IS  - 1078-0432
VI  - 9
IP  - 11
DP  - 2003 Sep 15
TI  - Differential vascular and transcriptional responses to anti-vascular
      endothelial growth factor antibody in orthotopic human pancreatic cancer
      xenografts.
PG  - 4221-6
AB  - PURPOSE: The objectives of this study were to investigate the effects of
      anti-vascular endothelial growth factor (VEGF) treatment on various
      vascular functions, gene expression, and growth of orthotopic human
      pancreatic cancer xenografts and thus to provide useful preclinical data
      for novel cancer treatments. EXPERIMENTAL DESIGN: Small pieces of a human
      pancreatic carcinoma, PANC-1, were implanted into the pancreas of male
      severe combined immunodeficient mice. The animals were treated with
      anti-human VEGF antibody A.4.6.1 (300 micro g, every 3 days i.p.) or a
      nonspecific IgG between 4 and 8 weeks after tumor implantation. Then,
      vascular density, diameter, permeability, and tumor growth were determined
      by intravital microscopy. Subsequently, tumors were harvested, and
      angiogenic gene expression profile was determined by a microarray kit
      including 96 genes involved in tumor angiogenesis. RESULTS: Anti-VEGF
      antibody significantly reduced angiogenesis and growth of orthotopic
      PANC-1 tumors. In the anti-VEGF treatment group, the vessel density was
      significantly smaller (67.8 +/- 10.6 cm/cm(2)) than that seen in the
      control group (146.7 +/- 10.0 cm/cm(2)). However, vessel diameter and
      permeability were not altered significantly by anti-VEGF antibody
      treatment. The pancreatic tumors in the treated group were significantly
      smaller than those in the control group. Microarray and subsequent
      Northern blot and semiquantitative reverse transcription-PCR analyses
      revealed both a decrease (fibroblast growth factor 1, transforming growth
      factor beta1, platelet-derived growth factor alpha, erbB2, and c-ets1,)
      and an increase (placenta growth factor, hypoxia-inducible factor alpha,
      and endoglin) in expression of angiogenesis-related genes in the PANC-1
      tumors by anti-VEGF treatment. CONCLUSIONS: Anti-VEGF antibody treatment
      has differential effects on vessel functions as well as angiogenic gene
      expression and inhibitory effects on angiogenesis and growth of the
      orthotopic pancreatic tumor. Anti-VEGF strategy appears promising for
      pancreatic cancer treatment.
AD  - Department of Radiation Oncology, Edwin L. Steele Laboratory,
      Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114, USA.
FAU - Bockhorn, Maximilian
AU  - Bockhorn M
FAU - Tsuzuki, Yoshikazu
AU  - Tsuzuki Y
FAU - Xu, Lei
AU  - Xu L
FAU - Frilling, Andreja
AU  - Frilling A
FAU - Broelsch, Christoph E
AU  - Broelsch CE
FAU - Fukumura, Dai
AU  - Fukumura D
LA  - eng
GR  - P01 CA 90124/CA/NCI
PT  - Journal Article
PL  - United States
TA  - Clin Cancer Res
JID - 9502500
RN  - 0 (Antibodies)
RN  - 0 (DNA Primers)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - Animals
MH  - Antibodies/*pharmacology
MH  - Base Sequence
MH  - Capillary Permeability/drug effects
MH  - Cell Division
MH  - DNA Primers
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Human
MH  - Male
MH  - Mice
MH  - Mice, SCID
MH  - Neovascularization, Pathologic/*genetics/pathology/*prevention & control
MH  - Neutralization Tests
MH  - Oligonucleotide Array Sequence Analysis
MH  - Pancreatic Neoplasms/*blood supply/*genetics/pathology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Support, Non-U.S. Gov't
MH  - Support, U.S. Gov't, P.H.S.
MH  - Transcription, Genetic/*genetics
MH  - Transplantation, Heterologous
MH  - Vascular Endothelial Growth Factor A/*immunology
EDAT- 2003/10/02 05:00
MHDA- 2004/08/18 05:00
PST - ppublish
SO  - Clin Cancer Res 2003 Sep 15;9(11):4221-6.

PMID- 13679997
OWN - NLM
STAT- completed
DA  - 20031013
DCOM- 20040621
IS  - 0946-2716
VI  - 81
IP  - 10
DP  - 2003 Oct
TI  - Inhibition of angiogenesis by NSAIDs: molecular mechanisms and clinical
      implications.
PG  - 627-36
AB  - Angiogenesis, the formation of new capillary blood vessels, is a
      fundamental process essential for reproduction and embryonic development.
      It is crucial to the healing of tissue injury because it provides
      essential oxygen and nutrients to the healing site. Angiogenesis is also
      required for cancer growth and progression since tumor growth requires an
      increased nutrient and oxygen supply. Nonsteroidal anti-inflammatory drugs
      (NSAIDs) are the most widely used drugs worldwide for treating pain,
      arthritis, cardiovascular diseases, and more recently for colon cancer
      prevention. However, NSAIDs produce gastrointestinal ulcers and delay
      ulcer healing. Recently NSAIDs have been demonstrated to inhibit
      angiogenesis, but the underlying mechanisms are only beginning to be
      elucidated. The inhibition of angiogenesis by NSAIDs is a causal factor in
      the delay of ulcer healing, and it is becoming clear that this is also
      likely to be one of the mechanisms by which NSAIDs can reduce or prevent
      cancer growth. Based on the experimental data and the literature, the
      mechanisms by which NSAIDs inhibit angiogenesis appear to be
      multifactorial and likely include local changes in angiogenic growth
      factor expression, alteration in key regulators and mediators of vascular
      endothelial growth factor (VEGF), increased endothelial cell apoptosis,
      inhibition of endothelial cell migration, recruitment of inflammatory
      cells and platelets, and/or thromboxane A2 mediated effects. Some of these
      mechanisms include: inhibition of mitogen-activated protein (Erk2) kinase
      activity; suppression of cell cycle proteins; inhibition of early growth
      response (Egr-1) gene activation; interference with hypoxia inducible
      factor 1 and VEGF gene activation; increased production of the
      angiogenesis inhibitor, endostatin; inhibition of endothelial cell
      proliferation, migration, and spreading; and induction of endothelial
      apoptosis.
AD  - Gastroenterology Section, VA Medical Center, 5901 E. Seventh Street, Long
      Beach, CA 90822, USA. andrzej.tarnawski@med.va.gov
FAU - Tarnawski, Andrzej S
AU  - Tarnawski AS
FAU - Jones, Michael K
AU  - Jones MK
LA  - eng
PT  - Journal Article
PT  - Review
PT  - Review, Tutorial
DEP - 20030906
PL  - Germany
TA  - J Mol Med
JID - 9504370
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (EGR1 protein, human)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.1.37 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/adverse effects/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Division/drug effects
MH  - DNA-Binding Proteins/antagonists & inhibitors
MH  - Endothelium, Vascular/drug effects
MH  - Human
MH  - Immediate-Early Proteins/antagonists & inhibitors
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors
MH  - Neoplasms/*blood supply
MH  - Neovascularization, Pathologic/enzymology/*prevention & control
MH  - Support, Non-U.S. Gov't
MH  - Support, U.S. Gov't, Non-P.H.S.
MH  - Transcription Factors/antagonists & inhibitors
RF  - 79
EDAT- 2003/09/19 05:00
MHDA- 2004/06/24 05:00
PHST- 2003/Jan/14 [received]
PHST- 2003/Jul/07 [accepted]
PHST- 2003/Sep/06 [aheadofprint]
AID - 10.1007/s00109-003-0479-y [doi]
PST - ppublish
SO  - J Mol Med 2003 Oct;81(10):627-36. Epub 2003 Sep 6.

PMID- 12925145
OWN - NLM
STAT- completed
DA  - 20030819
DCOM- 20030916
LR  - 20031114
IS  - 0269-2813
VI  - 18 Suppl 1
DP  - 2003 Jul
TI  - The specific expression of hypoxia inducible factor-1alpha in human
      gastric mucosa induced by nonsteroidal anti-inflammatory drugs.
PG  - 90-8
AB  - BACKGROUND: Hypoxia is a cause of gastric mucosal damage induced by
      nonsteroidal anti-inflammatory drugs (NSAIDs). The expression of hypoxia
      inducible factor-1alpha (HIF-1alpha) reflects the status of tissue
      ischaemia. AIM: To investigate the effect of NSAID administration on the
      expression of HIF-1alpha in human gastric mucosa. METHODS: We employed 71
      patients including 14 with NSAID administration. The HIF-1alpha expression
      was estimated by immunohistochemistry using monoclonal antibody
      (H1alpha67) and raised antiserum (HI-3). Vascular endothelial growth
      factor expression was also examined by immunohistochemistry. HI-3
      recognized hypoxia-induced protein in HeLa cells. RESULTS: In human
      gastric mucosa, HIF-1alpha was mainly expressed in the nuclei of the
      surface epithelial cells and in the neck zone both by use of HI-3 and of
      H1alpha67. The expression of vascular endothelial growth factor correlated
      well with that of HIF-1alpha. The level of HIF-1alpha in the surface
      epithelium was significantly higher in patients with administration of
      NSAIDs than those without NSAID use (P < 0.001) both in the gastric corpus
      and antrum. Helicobacter pylori infection did not affected the levels of
      HIF-1alpha. Long-term administration of rebamipide reduced the level of
      HIF-1alpha. CONCLUSION: HIF-1alpha expression is a new biological marker
      of ischaemia especially in NSAID-related gastric lesions.
AD  - Department of Medicine and Molecular Science, Graduate School of
      Biomedical Science, Hiroshima University, Hiroshima, Japan.
      maito@hiroshima-u.ac.jp
FAU - Ito, M
AU  - Ito M
FAU - Tanaka, S
AU  - Tanaka S
FAU - Kim, S
AU  - Kim S
FAU - Kuwai, T
AU  - Kuwai T
FAU - Matsutani, N
AU  - Matsutani N
FAU - Kamada, T
AU  - Kamada T
FAU - Kitadai, Y
AU  - Kitadai Y
FAU - Sumii, M
AU  - Sumii M
FAU - Yoshihara, M
AU  - Yoshihara M
FAU - Haruma, K
AU  - Haruma K
FAU - Chayama, K
AU  - Chayama K
LA  - eng
PT  - Journal Article
PL  - England
TA  - Aliment Pharmacol Ther
JID - 8707234
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Anti-Ulcer Agents)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Quinolones)
RN  - 0 (Transcription Factors)
RN  - 111911-87-6 (rebamipide)
RN  - 56-41-7 (Alanine)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Alanine/*analogs & derivatives/pharmacology
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Anti-Ulcer Agents/pharmacology
MH  - Blotting, Western
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Gastric Mucosa/*metabolism
MH  - Human
MH  - Immunohistochemistry
MH  - Male
MH  - Middle Aged
MH  - Quinolones/pharmacology
MH  - Transcription Factors/*metabolism
EDAT- 2003/08/20 05:00
MHDA- 2003/09/17 05:00
AID - 1511 [pii]
PST - ppublish
SO  - Aliment Pharmacol Ther 2003 Jul;18 Suppl 1:90-8.

PMID- 12865631
OWN - NLM
STAT- completed
DA  - 20030716
DCOM- 20040217
IS  - 1015-2008
VI  - 70
IP  - 6
DP  - 2002-2003
TI  - A role of histone H4 hypoacetylation in vascular endothelial growth factor
      expression in colon mucosa adjacent to implanted cancer in athymic mice
      cecum.
PG  - 348-52
AB  - Expression of angiogenic factors is upregulated in hyperplastic mucosa
      adjacent to colon cancer, and this upregulation is closely associated with
      cancer growth and metastasis. We investigated the role of histone
      acetylation in vascular endothelial growth factor (VEGF) expression in
      hyperplastic mucosa adjacent to orthotopic colon cancer in mice. In the
      hyperplastic mucosa adjacent to KM12SM tumor in the cecum of athymic mice,
      VEGF upregulation was associated with hypoxia-inducible factor
      (HIF)-1alpha induction. The hyperplastic mucosa also showed
      hypoacetylation of histone H4 and reduction of both p53 and von
      Hippel-Lindau (VHL) proteins. To examine the effects of growth factors and
      cytokines on histone acetylation and levels of p53, VHL and HIF-1alpha,
      the rat intestinal epithelial cell line IEC6 was treated with epidermal
      growth factor (EGF) and interleukin (IL)-15 for 35 days. Acetylated
      histone H4, p53 protein and ubiquitinated protein levels were reduced,
      whereas HIF-1alpha production was upregulated in EGF- and IL-15-treated
      IEC6 cells. These findings suggest that EGF- or IL-15-induced histone H4
      hypoacetylation is associated with repression of p53 and VHL genes in
      intestinal epithelial cells. The subsequent suppression of protein
      ubiquitination leads to upregulation of VEGF production by HIF-1alpha
      retention.
CI  - Copyright 2003 S. Karger AG, Basel
AD  - Department of Oncological Pathology, Cancer Center, Nara Medical
      University, Kashihara, Japan. cooninh@zb4.so-net.ne.jp
FAU - Kuniyasu, Hiroki
AU  - Kuniyasu H
FAU - Chihara, Yoshitomo
AU  - Chihara Y
FAU - Kondo, Hideaki
AU  - Kondo H
LA  - eng
PT  - Journal Article
PL  - Switzerland
TA  - Pathobiology
JID - 9007504
RN  - 0 (HIF1alpha protein)
RN  - 0 (Histones)
RN  - 0 (Interleukin-15)
RN  - 0 (Protein p53)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (vascular endothelial growth factor A, mouse)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 6.3.2.19 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Acetylation
MH  - Animals
MH  - Cell Line, Tumor
MH  - Colon/*metabolism/pathology
MH  - *Colonic Neoplasms/pathology
MH  - Epidermal Growth Factor/pharmacology
MH  - *Epigenesis, Genetic
MH  - Fluorescent Antibody Technique, Indirect
MH  - Histones/*metabolism
MH  - Human
MH  - Hyperplasia
MH  - Interleukin-15/pharmacology
MH  - Intestinal Mucosa/drug effects/*metabolism/pathology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Neoplasm Transplantation
MH  - Protein p53/metabolism
MH  - Rats
MH  - Specific Pathogen-Free Organisms
MH  - Support, Non-U.S. Gov't
MH  - Transcription Factors/metabolism
MH  - Ubiquitin-Protein Ligases/metabolism
MH  - Up-Regulation
MH  - Vascular Endothelial Growth Factor A/*metabolism
EDAT- 2003/07/17 05:00
MHDA- 2004/02/18 05:00
PHST- 2002/Nov/28 [received]
PHST- 2003/Feb/07 [accepted]
AID - 10.1159/000071275 [doi]
AID - PAT2002070006348 [pii]
PST - ppublish
SO  - Pathobiology 2002-2003;70(6):348-52.

PMID- 12792726
OWN - NLM
STAT- completed
DA  - 20030606
DCOM- 20040206
IS  - 1021-335X
VI  - 10
IP  - 4
DP  - 2003 Jul-Aug
TI  - Hypoxia-inducible factor-1alpha expression and angiogenesis in
      gastrointestinal stromal tumor of the stomach.
PG  - 797-802
AB  - Hypoxia inducible factor (HIF)-1 is reported to transactivate expression
      of vascular endothelial growth factor (VEGF), which is an important
      angiogenic factor. The aim of this study was to elucidate the clinical
      significance of HIF-1alpha expression in gastrointestinal stromal tumors
      (GIST). Specimens obtained from 53 patients who underwent surgical
      resection for GIST of the stomach were used in this study. Specimens were
      examined immunohistochemically for HIF-1alpha, VEGF, and Ki-67 expression.
      Tumor microvessel density (MVD) was determined immunohistochemically with
      anti-CD31 antibody and was estimated by averaging the counts from three
      high-power fields in the area showing the greatest neovascularization.
      HIF-1alpha expression was detected in 17 (32.1%) of 53 lesions and was
      correlated significantly with tumor size, liver metastasis, VEGF
      expression, and MVD. Prognosis was significantly poorer in patients with
      tumors expressing HIF-1alpha than in patients with tumors lacking
      HIF-1alpha expression. HIF-1alpha may play a role in angiogenesis and
      tumor progression of GIST through regulation of VEGF.
AD  - Department of Medicine and Molecular Science, Division of Frontier Medical
      Science, Programs for Biomedical Research, Graduate School of Biomedical
      Science, Hiroshima University, Hiroshima, Japan.
FAU - Takahashi, Ryoji
AU  - Takahashi R
FAU - Tanaka, Shinji
AU  - Tanaka S
FAU - Hiyama, Toru
AU  - Hiyama T
FAU - Ito, Masanori
AU  - Ito M
FAU - Kitadai, Yasuhiko
AU  - Kitadai Y
FAU - Sumii, Masaharu
AU  - Sumii M
FAU - Haruma, Ken
AU  - Haruma K
FAU - Chayama, Kazuaki
AU  - Chayama K
LA  - eng
PT  - Journal Article
PL  - Greece
TA  - Oncol Rep
JID - 9422756
RN  - 0 (HIF1alpha protein)
RN  - 0 (Ki-67 Antigen)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Female
MH  - Human
MH  - Immunoenzyme Techniques
MH  - Ki-67 Antigen/metabolism
MH  - Male
MH  - Middle Aged
MH  - Neovascularization, Pathologic/*metabolism
MH  - Prognosis
MH  - Stomach Neoplasms/*blood supply/*metabolism
MH  - *Stromal Cells
MH  - Survival Rate
MH  - Transcription Factors/*metabolism
MH  - Vascular Endothelial Growth Factor A/*metabolism
EDAT- 2003/06/07 05:00
MHDA- 2004/02/10 05:00
PST - ppublish
SO  - Oncol Rep 2003 Jul-Aug;10(4):797-802.

PMID- 12773481
OWN - NLM
STAT- completed
DA  - 20030529
DCOM- 20030625
LR  - 20040212
IS  - 1530-6860
VI  - 17
IP  - 9
DP  - 2003 Jun
TI  - CD105 is important for angiogenesis: evidence and potential applications.
PG  - 984-92
AB  - Angiogenesis is the propelling force for tumor growth and metastasis, and
      antiangiogenic therapy represents one of the most promising modalities for
      cancer treatment. CD105 (endoglin) is a proliferation-associated and
      hypoxia-inducible protein abundantly expressed in angiogenic endothelial
      cells (EC). It is a receptor for transforming growth factor (TGF) -beta1
      and -beta3 and modulates TGF-beta signaling by interacting with TGF-beta
      receptors I and/or II. Immunohistochemistry studies have revealed that
      CD105 is strongly expressed in blood vessels of tumor tissues.
      Intratumoral microvessel density (MVD) determined using antibodies to
      CD105 has been found to be an independent prognostic indicator, wherein
      increased MVD correlates with shorter survival. CD105 is able to be shed
      into the circulation, with elevated levels detected in patients with
      various types of cancer and positively correlated with tumor metastasis.
      Tangible evidence of its proangiogenic role comes from knockout studies in
      which CD105 null mice die in utero as a result of impaired angiogenesis in
      the yolk sac and heart defects. The potential usefulness of CD105 for
      tumor imaging has been evaluated in tumor-bearing mice and dogs that have
      shown the rapid accumulation of radiolabeled anti-CD105 monoclonal
      antibody in the tumors with a high tumor-to-background ratio. The
      anti-CD105 antibody conjugated with immunotoxins and immunoradioisotopes
      efficiently suppressed/abrogated tumor growth in murine models bearing
      breast and colon carcinoma without any significant systemic side effects.
      Immunoscintigraphy in patients with renal cell carcinomas has shown
      specific localization of 99Tcm-labeled CD105 mab in tumor endothelial
      cells. Thus, CD105 is a promising vascular target that can be used for
      tumor imaging, prognosis, and bears therapeutic potential in patients with
      solid tumors and other angiogenic diseases.
AD  - Department of Pathology, Medical School, University of Manchester, M13
      9PT, UK.
FAU - Duff, Sarah E
AU  - Duff SE
FAU - Li, Chenggang
AU  - Li C
FAU - Garland, John M
AU  - Garland JM
FAU - Kumar, Shant
AU  - Kumar S
LA  - eng
PT  - Journal Article
PT  - Review
PT  - Review, Tutorial
PL  - United States
TA  - FASEB J
JID - 8804484
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (ENG protein, human)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
SB  - IM
MH  - Angiogenesis Inhibitors/therapeutic use
MH  - Animals
MH  - Drug Delivery Systems
MH  - Gene Expression Regulation
MH  - Human
MH  - Mice
MH  - Mutation
MH  - Neoplasms/*blood supply/diagnosis/therapy
MH  - *Neovascularization, Pathologic
MH  - Neovascularization, Physiologic
MH  - Radioimmunodetection
MH  - Signal Transduction
MH  - Telangiectasia, Hereditary Hemorrhagic/genetics
MH  - Vascular Cell Adhesion Molecule-1/analysis/genetics/*physiology
RF  - 80
EDAT- 2003/05/30 05:00
MHDA- 2003/06/26 05:00
AID - 10.1096/fj.02-0634rev [doi]
AID - 17/9/984 [pii]
PST - ppublish
SO  - FASEB J 2003 Jun;17(9):984-92.

PMID- 12727858
OWN - NLM
STAT- completed
DA  - 20030502
DCOM- 20030616
LR  - 20040719
IS  - 0008-5472
VI  - 63
IP  - 9
DP  - 2003 May 1
TI  - Vascular endothelial growth factor gene expression in colon cancer cells
      exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1.
PG  - 2330-4
AB  - Prostaglandin E(2) (PGE(2)) has been implicated as an inducer of
      angiogenesis in human colon cancer. Here, we demonstrate that PGE(2)
      exposure induces the expression of vascular endothelial growth factor
      (VEGF) mRNA in HCT116 human colon carcinoma cells that is mediated by the
      transcriptional activator hypoxia-inducible factor 1 (HIF-1). PGE(2)
      exposure induces the phosphorylation of extracellular signal-regulated
      kinase (ERK) and AKT. Pharmacologic inhibition of ERK phosphorylation
      blocks the induction of VEGF mRNA and HIF-1alpha protein expression in
      response to PGE(2) stimulation. Inhibition of C-SRC tyrosine kinase
      activity also blocks PGE(2)-induced HIF-1alpha protein and VEGF mRNA
      expression without blocking ERK phosphorylation. In contrast,
      phosphorylation of AKT is dependent on ERK and C-SRC activity. Thus, the
      activity of multiple signal transduction pathways is required for the
      HIF-1-mediated induction of VEGF expression in colon cancer cells exposed
      to PGE(2).
AD  - McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins
      University School of Medicine, Baltimore, Maryland 21287-3914, USA.
FAU - Fukuda, Ryo
AU  - Fukuda R
FAU - Kelly, Brian
AU  - Kelly B
FAU - Semenza, Gregg L
AU  - Semenza GL
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JID - 2984705R
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lymphokines)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 363-24-6 (Dinoprostone)
RN  - EC 2.7.1.112 (Protein-Tyrosine Kinase)
RN  - EC 2.7.1.112 (protein-tyrosine kinase c-src)
RN  - EC 2.7.1.37 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.1.37 (proto-oncogene protein akt)
SB  - IM
MH  - Colonic Neoplasms/genetics/*metabolism
MH  - Dinoprostone/*pharmacology
MH  - Endothelial Growth Factors/*biosynthesis/genetics
MH  - Gene Expression Regulation, Neoplastic/drug effects/physiology
MH  - Human
MH  - Intercellular Signaling Peptides and Proteins/*biosynthesis/genetics
MH  - Lymphokines/*biosynthesis/genetics
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Phosphorylation
MH  - Protein-Tyrosine Kinase/antagonists & inhibitors/metabolism
MH  - Proto-Oncogene Proteins/metabolism
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Support, U.S. Gov't, P.H.S.
MH  - Transcription Factors/antagonists & inhibitors/biosynthesis/*physiology
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2003/05/03 05:00
MHDA- 2003/06/17 05:00
PST - ppublish
SO  - Cancer Res 2003 May 1;63(9):2330-4.

PMID- 12671019
OWN - NLM
STAT- completed
DA  - 20030402
DCOM- 20030424
LR  - 20031114
IS  - 0027-8874
VI  - 95
IP  - 7
DP  - 2003 Apr 2
TI  - YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1.
PG  - 516-25
AB  - BACKGROUND: Hypoxia-inducible factor 1 alpha (HIF-1alpha), a component of
      HIF-1, is expressed in human tumors and renders cells able to survive and
      grow under hypoxic (low-oxygen) conditions. YC-1,
      3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole, an agent developed for
      circulatory disorders that inhibits platelet aggregation and vascular
      contraction, inhibits HIF-1 activity in vitro. We tested whether YC-1
      inhibits HIF-1 and tumor growth in vivo. METHODS: Hep3B hepatoma, NCI-H87
      stomach carcinoma, Caki-1 renal carcinoma, SiHa cervical carcinoma, and
      SK-N-MC neuroblastoma cells were grown as xenografts in immunodeficient
      mice (69 mice total). After the tumors were 100-150 mm(3), mice received
      daily intraperitoneal injections of vehicle or YC-1 (30 microg/g) for 2
      weeks. HIF-1 alpha protein levels and vascularity in tumors were assessed
      by immunohistochemistry, and the expression of HIF-1-inducible genes
      (vascular endothelial growth factor, aldolase, and enolase) was assessed
      by reverse transcription-polymerase chain reaction. All statistical tests
      were two-sided. RESULTS: Compared with tumors from vehicle-treated mice,
      tumors from YC-1-treated mice were statistically significantly smaller
      (P<.01 for all comparisons), expressed lower levels of HIF-1 alpha (P<.01
      for all comparisons), were less vascularized (P<.01 for all comparisons),
      and expressed lower levels of HIF-1-inducible genes, regardless of tumor
      type. CONCLUSIONS: The inhibition of HIF-1 alpha activity in tumors from
      YC-1-treated mice is associated with blocked angiogenesis and an
      inhibition of tumor growth. YC-1 has the potential to become the first
      antiangiogenic anticancer agent to target HIF-1 alpha.
AD  - Department of Pharmacology, BK21 Human Life Sciences, Seoul National
      University College of Medicine, Seoul, Korea.
FAU - Yeo, Eun-Jin
AU  - Yeo EJ
FAU - Chun, Yang-Sook
AU  - Chun YS
FAU - Cho, Young-Suk
AU  - Cho YS
FAU - Kim, Jinho
AU  - Kim J
FAU - Lee, June-Chul
AU  - Lee JC
FAU - Kim, Myung-Suk
AU  - Kim MS
FAU - Park, Jong-Wan
AU  - Park JW
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Natl Cancer Inst
JID - 7503089
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antigens, CD31)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Indazoles)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lymphokines)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 154453-18-6 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole)
RN  - 37758-47-7 (G(M1) Ganglioside)
RN  - 71012-19-6 (asialo GM1 ganglioside)
SB  - IM
CIN - J Natl Cancer Inst. 2003 Apr 2;95(7):498-9. PMID: 12671009
MH  - Angiogenesis Inhibitors/*pharmacology
MH  - Animals
MH  - Antigens, CD31/analysis
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma/drug therapy
MH  - Carcinoma, Hepatocellular/drug therapy
MH  - Cell Hypoxia/drug effects
MH  - Cervix Neoplasms/drug therapy
MH  - Culture Media, Conditioned
MH  - Endothelial Growth Factors/analysis
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - G(M1) Ganglioside/analysis
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Human
MH  - Immunoblotting
MH  - Indazoles/*pharmacology
MH  - Intercellular Signaling Peptides and Proteins/analysis
MH  - Kidney Neoplasms/drug therapy
MH  - Killer Cells, Natural/drug effects/metabolism
MH  - Liver Neoplasms/drug therapy
MH  - Lymphokines/analysis
MH  - Male
MH  - Mice
MH  - Mice, SCID
MH  - Neoplasms/blood supply/*drug therapy/metabolism
MH  - Neovascularization, Pathologic/metabolism/*prevention & control
MH  - Neuroblastoma/drug therapy
MH  - Precipitin Tests
MH  - Rats
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Stomach Neoplasms/drug therapy
MH  - Transcription Factors/*drug effects/*metabolism
MH  - Transplantation, Heterologous
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2003/04/03 05:00
MHDA- 2003/04/25 05:00
PST - ppublish
SO  - J Natl Cancer Inst 2003 Apr 2;95(7):516-25.

PMID- 12657718
OWN - NLM
STAT- completed
DA  - 20030326
DCOM- 20031211
LR  - 20040818
IS  - 1535-7163
VI  - 2
IP  - 3
DP  - 2003 Mar
TI  - The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and
      pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial
      growth factor formation.
PG  - 235-43
AB  - Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a
      critical role in tumor growth by increasing resistance to apoptosis and
      the production of angiogenic factors such as vascular endothelial growth
      factor (VEGF). HIF-1 is a heterodimer comprised of oxygen-regulated
      HIF-1alpha and constitutively expressed HIF-1beta subunits. The redox
      protein thioredoxin-1 (Trx-1), which is found at high levels in many human
      cancers, increases both aerobic and hypoxia-induced HIF-1alpha protein in
      cells leading to increased expression of HIF-regulated genes. We have
      investigated whether two cancer drugs that inhibit Trx-1 signaling, PX-12
      (1-methylpropyl 2-imidazolyl disulfide) and pleurotin, decrease HIF-1alpha
      protein levels and the expression of downstream target genes. Treatment of
      MCF-7 human breast cancer and HT-29 human colon carcinoma cells with PX-12
      and pleurotin prevented the hypoxia (1% oxygen)-induced increase in
      HIF-1alpha protein. HIF-1-trans-activating activity, VEGF formation, and
      inducible nitric oxide synthase were also decreased by treatment with
      PX-12 and pleurotin under hypoxic conditions. PX-12 and pleurotin also
      decreased HIF-1alpha protein levels and HIF-1 trans-activation in RCC4
      renal cell carcinoma cells that constitutively overexpress HIF-1alpha
      protein because of loss of the pVHL gene, indicating that HIF-1alpha is
      inhibited independently of the pVHL pathway. HIF-1alpha and VEGF protein
      levels in MCF-7 tumor xenografts in vivo were decreased by PX-12 treatment
      of mice. The results suggest that inhibition of HIF-1alpha by Trx-1
      inhibitors may contribute to the growth inhibitory and antitumor activity
      of these agents.
AD  - Arizona Cancer Center, Tucson, Arizona 85724, USA. swelsh@azcc.arizona.edu
FAU - Welsh, Sarah J
AU  - Welsh SJ
FAU - Williams, Ryan R
AU  - Williams RR
FAU - Birmingham, Anne
AU  - Birmingham A
FAU - Newman, David J
AU  - Newman DJ
FAU - Kirkpatrick, D Lynn
AU  - Kirkpatrick DL
FAU - Powis, Garth
AU  - Powis G
LA  - eng
GR  - CA17094/CA/NCI
GR  - CA52995/CA/NCI
GR  - CA98920/CA/NCI
PT  - Journal Article
PL  - United States
TA  - Mol Cancer Ther
JID - 101132535
RN  - 0 (Disulfides)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Heterocyclic Compounds with 4 or More Rings)
RN  - 0 (IV 2 compound)
RN  - 0 (Imidazoles)
RN  - 0 (Membrane Proteins)
RN  - 0 (TRX1 protein, S cerevisiae)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (pleurotin)
RN  - 52500-60-4 (Thioredoxin)
RN  - EC 1.13.12.- (Luciferase)
RN  - EC 1.14.13.- (inducible nitric oxide synthase)
RN  - EC 1.14.13.39 (Nitric-Oxide Synthase)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Breast Neoplasms/metabolism
MH  - Cell Division/drug effects
MH  - Colonic Neoplasms/metabolism
MH  - Disulfides/*pharmacology
MH  - Down-Regulation
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Heterocyclic Compounds with 4 or More Rings/*pharmacology
MH  - Human
MH  - Imidazoles/*pharmacology
MH  - Immunoenzyme Techniques
MH  - Kidney Neoplasms/metabolism
MH  - Luciferase/metabolism
MH  - Membrane Proteins/*antagonists & inhibitors
MH  - Mice
MH  - Mice, SCID
MH  - Nitric-Oxide Synthase/metabolism
MH  - Support, U.S. Gov't, P.H.S.
MH  - Thioredoxin/*antagonists & inhibitors/metabolism
MH  - Transcription Factors/*antagonists & inhibitors
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A/*antagonists & inhibitors
EDAT- 2003/03/27 05:00
MHDA- 2003/12/12 05:00
PST - ppublish
SO  - Mol Cancer Ther 2003 Mar;2(3):235-43.

PMID- 12615733
OWN - NLM
STAT- completed
DA  - 20030304
DCOM- 20030401
LR  - 20031114
IS  - 0008-5472
VI  - 63
IP  - 5
DP  - 2003 Mar 1
TI  - Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1.
PG  - 1138-43
AB  - Hypoxia-inducible factor 1 (HIF-1) transactivates genes the products of
      which mediate tumor angiogenesis and glycolytic metabolism. Overexpression
      of the HIF-1 alpha subunit, resulting from intratumoral hypoxia and
      genetic alterations, has been demonstrated in common human cancers and is
      correlated with tumor angiogenesis and patient mortality. Here we
      demonstrate that hypoxia or HIF-1 alpha overexpression stimulates Matrigel
      invasion by HCT116 human colon carcinoma cells, whereas this process is
      inhibited by a small interfering RNA directed against HIF-1 alpha. We show
      that HIF-1 regulates the expression of genes encoding cathepsin D; matrix
      metalloproteinase 2; urokinase plasminogen activator receptor (uPAR);
      fibronectin 1; keratins 14, 18, and 19; vimentin; transforming growth
      factor alpha; and autocrine motility factor, which are proteins that play
      established roles in the pathophysiology of invasion. Neutralizing
      antibodies against uPAR block tumor cell invasion induced by hypoxia or
      HIF-1 alpha overexpression. These results provide a molecular basis for
      promotion of the invasive cancer phenotype by hypoxia and/or HIF-1 alpha
      overexpression.
AD  - McKusick-Nathans Institute of Genetic Medicine and Department of
      Pediatrics, The Johns Hopkins University School of Medicine, Baltimore,
      Maryland 21287-3914, USA.
FAU - Krishnamachary, Balaji
AU  - Krishnamachary B
FAU - Berg-Dixon, Shannon
AU  - Berg-Dixon S
FAU - Kelly, Brian
AU  - Kelly B
FAU - Agani, Faton
AU  - Agani F
FAU - Feldser, David
AU  - Feldser D
FAU - Ferreira, Gloria
AU  - Ferreira G
FAU - Iyer, Narayan
AU  - Iyer N
FAU - LaRusch, Jessica
AU  - LaRusch J
FAU - Pak, Brian
AU  - Pak B
FAU - Taghavi, Panthea
AU  - Taghavi P
FAU - Semenza, Gregg L
AU  - Semenza GL
LA  - eng
GR  - P20-CA86346/CA/NCI
GR  - R01-HL55338/HL/NHLBI
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JID - 2984705R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF-1 protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (plasminogen activator, urokinase receptors)
SB  - IM
MH  - Animals
MH  - Basement Membrane/cytology/metabolism
MH  - Cell Hypoxia/physiology
MH  - Colonic Neoplasms/genetics/metabolism/*pathology
MH  - DNA-Binding Proteins/biosynthesis/genetics/*physiology
MH  - Gene Expression Regulation, Neoplastic
MH  - Human
MH  - Mice
MH  - Neoplasm Invasiveness
MH  - Nuclear Proteins/biosynthesis/genetics/*physiology
MH  - Receptors, Cell Surface/biosynthesis/genetics/physiology
MH  - Support, Non-U.S. Gov't
MH  - Support, U.S. Gov't, P.H.S.
MH  - Transfection
MH  - Tumor Cells, Cultured
EDAT- 2003/03/05 04:00
MHDA- 2003/04/02 05:00
PST - ppublish
SO  - Cancer Res 2003 Mar 1;63(5):1138-43.

PMID- 12610101
OWN - NLM
STAT- completed
DA  - 20030228
DCOM- 20030326
LR  - 20031114
IS  - 0021-9746
VI  - 56
IP  - 3
DP  - 2003 Mar
TI  - Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory
      bowel disease.
PG  - 209-13
AB  - AIMS: Hypoxia inducible factors 1alpha and 2alpha (HIF1alpha and
      HIF2alpha) are hypoxia regulated transcriptional factors, which control
      the expression of a variety of genes responsible for angiogenesis,
      glycolysis, and the inhibition of apoptosis. Because angiogenesis and
      tissue regeneration are integral components of the inflammatory process,
      this study was designed to investigate the role of HIFalpha molecules in
      inflammatory bowel disease. METHODS: Surgical specimens from patients with
      active ulcerative colitis (UC) and Crohn's disease (CD) were assessed
      immunohistochemically for HIF1alpha and HIF2alpha reactivity, and the
      expression of these molecules was compared with the expression of the
      angiogenic factors thymidine phosphorylase (TP), vascular endothelial
      growth factor (VEGF), and VEGF-KDR activated vasculature. The vascular
      density of the lesions was also assessed using anti-CD31 immunostaining.
      RESULTS: HIF1alpha was expressed focally (epithelial cells, stromal
      fibroblasts, and myocytes) in both UC and CD, whereas HIF2alpha was
      expressed focally in UC and diffusely in CD. TP expression was uniformly
      positive in both diseases. VEGF expression was absent in CD, and weakly
      positive in UC. The VEGF-KDR reactivity of the submucosal vasculature was
      only slightly increased in UC and CD compared with normal tissue. The
      inflammatory cells stained with HIF2alpha and TP in all cases, but the
      reactivity was generalised in CD and focal in UC. In both diseases,
      vascular density was significantly higher than that seen in normal tissue.
      CONCLUSIONS: The discordant expression of HIF2alpha and VEGF in CD
      suggests an inherent deficiency of the intestine to respond to various
      stresses by the induction of VEGF. This finding should be investigated
      further.
AD  - Department of Pathology, Democritus University of Thrace, PO Box 12,
      Alexandroupolis 68100, Greece. targ@her.forthnet.gr
FAU - Giatromanolaki, A
AU  - Giatromanolaki A
FAU - Sivridis, E
AU  - Sivridis E
FAU - Maltezos, E
AU  - Maltezos E
FAU - Papazoglou, D
AU  - Papazoglou D
FAU - Simopoulos, C
AU  - Simopoulos C
FAU - Gatter, K C
AU  - Gatter KC
FAU - Harris, A L
AU  - Harris AL
FAU - Koukourakis, M I
AU  - Koukourakis MI
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Clin Pathol
JID - 0376601
RN  - 0 (Angiogenesis Inducing Agents)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF-1 protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Trans-Activators)
RN  - 0 (bHLH-PAS factor HLF)
SB  - AIM
SB  - IM
MH  - Adult
MH  - Aged
MH  - Angiogenesis Inducing Agents/metabolism
MH  - Antibodies, Monoclonal/immunology
MH  - Colitis, Ulcerative/metabolism
MH  - Colon/blood supply
MH  - Crohn Disease/metabolism
MH  - DNA-Binding Proteins/*metabolism
MH  - Female
MH  - Human
MH  - Immunoenzyme Techniques
MH  - Inflammatory Bowel Diseases/*metabolism
MH  - Intestinal Mucosa/blood supply/metabolism
MH  - Male
MH  - Middle Aged
MH  - Neovascularization, Pathologic/metabolism
MH  - Nuclear Proteins/*metabolism
MH  - Support, Non-U.S. Gov't
MH  - Trans-Activators/*metabolism
EDAT- 2003/03/01 04:00
MHDA- 2003/03/27 05:00
PST - ppublish
SO  - J Clin Pathol 2003 Mar;56(3):209-13.

PMID- 12539169
OWN - NLM
STAT- completed
DA  - 20030122
DCOM- 20030717
LR  - 20040520
IS  - 1059-910X
VI  - 60
IP  - 2
DP  - 2003 Feb 1
TI  - Von Hippel-Lindau disease.
PG  - 159-64
AB  - Von Hippel-Lindau (VHL) disease is an uncommon, autosomal dominant
      hereditary multitumor syndrome caused by germline alterations of the VHL
      gene, which has been cloned recently and identified as a tumor suppressor
      gene. The major lesions in VHL disease include hemangioblastomas in the
      central nervous system and retina, clear cell renal cell carcinomas,
      pheochromocytomas, pancreatic tumors, epididymal cystadenomas,
      endolymphatic sac tumors, carcinoid tumors, and multiple cysts of the
      kidney, pancreas, and epididymis. Compared with sporadic ones, the tumors
      in VHL disease develop at an earlier age and often multifocally.
      Histologic features of VHL tumors are characterized by their high degree
      of vascularization and the presence of a clear cell component.
      Hypervascularization is induced by overexpression of vascular endothelial
      growth factor (VEGF), and because the principal function of VHL protein is
      the negative regulation of hypoxia-inducible mRNAs including VEGF mRNA,
      inactivation of VHL gene plays critical roles in angiogenesis of the VHL
      tumors. In addition, since VHL protein is also required for the
      down-regulation of transcription activity of certain genes for the cell
      growth and cell cycle, inactivation of VHL gene may contribute to
      tumorigenesis of the VHL tumors. A significant difference in the frequency
      of types of VHL gene mutation has been noted among the affected families,
      known as the genotype-phenotype correlations.
CI  - Copyright 2003 Wiley-Liss, Inc.
AD  - Department of Pathology, University of Tokushima School of Medicine,
      Tokushima 770-8503, Japan. sano@basic.med.tokushima-u.ac.jp
FAU - Sano, Toshiaki
AU  - Sano T
FAU - Horiguchi, Hidehisa
AU  - Horiguchi H
LA  - eng
PT  - Journal Article
PT  - Review
PT  - Review, Tutorial
PL  - United States
TA  - Microsc Res Tech
JID - 9203012
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lymphokines)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - EC 6. (Ligases)
RN  - EC 6.3.2.19 (Ubiquitin-Protein Ligases)
RN  - EC 6.3.2.19 (VHL protein, human)
SB  - IM
MH  - Central Nervous System Neoplasms/blood supply/pathology
MH  - Endothelial Growth Factors/*biosynthesis
MH  - Hemangioblastoma/pathology
MH  - *Hippel-Lindau Disease
MH  - Human
MH  - Intercellular Signaling Peptides and Proteins/*biosynthesis
MH  - Ligases/*genetics
MH  - Lymphokines/*biosynthesis
MH  - *Tumor Suppressor Proteins
MH  - *Ubiquitin-Protein Ligases
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
RF  - 62
EDAT- 2003/01/23 04:00
MHDA- 2003/07/18 05:00
AID - 10.1002/jemt.10253 [doi]
PST - ppublish
SO  - Microsc Res Tech 2003 Feb 1;60(2):159-64.

PMID- 12538497
OWN - NLM
STAT- completed
DA  - 20030122
DCOM- 20030717
LR  - 20031114
IS  - 1078-0432
VI  - 9
IP  - 1
DP  - 2003 Jan
TI  - Gastric epithelial reactive oxygen species prevent normoxic degradation of
      hypoxia-inducible factor-1alpha in gastric cancer cells.
PG  - 433-40
AB  - The expression of hypoxia inducible factor (HIF)-1alpha protein is tightly
      regulated by cellular oxygen status. Namely, HIF-1alpha protein is
      degraded rapidly in normoxic cells, whereas hypoxia stabilizes HIF-1alpha
      to transactivate hypoxia-responsive genes. Here we show that HIF-1alpha
      protein is expressed aberrantly in gastric cancer cells under normoxia in
      a reactive oxygen species (ROS)-dependent manner. The normoxic expression
      of HIF-1alpha in concordance with its DNA binding activity enhances the
      transcription of target genes such as vascular endothelial growth factor.
      The aberrant normoxic expression of HIF-1alpha is not associated with
      genetic abnormalities such as the loss of von Hippel-Lindau tumor
      suppressor, but is well correlated with endogenous ROS (hydrogen peroxide)
      generation. HIF-1alpha expression is blocked by nonmitochondrial ROS
      inhibitors, but not by inhibitors of mitochondrial electron transfer,
      which indicates that nonmitochondrial ROS stabilize HIF-1alpha protein in
      these cells. Gastric epithelial ROS have been linked to Helicobacter
      pylori-induced gastric carcinogenesis. This study demonstrates for the
      first time that ROS from H. pylori-infected gastric epithelial cells
      induce HIF-1alpha expression and subsequently activate HIF-1alpha-mediated
      transcription. Taken together, these results provide a novel mechanism of
      HIF-1alpha stabilization in gastric cancer, and demonstrate that gastric
      epithelial ROS, endogenously generated or H. pylori-stimulated, lead to
      the constant expression of HIF-1alpha protein under normoxia.
AD  - Department of Tumor Biology, Seoul National University College of
      Medicine, Seoul 110-799, Korea.
FAU - Park, Jung-Hyun
AU  - Park JH
FAU - Kim, Tae-You
AU  - Kim TY
FAU - Jong, Hyun-Soon
AU  - Jong HS
FAU - Kim, Tai Young
AU  - Kim TY
FAU - Chun, Yang-Sook
AU  - Chun YS
FAU - Park, Jong-Wan
AU  - Park JW
FAU - Lee, Choon-Taek
AU  - Lee CT
FAU - Jung, Hyun Chae
AU  - Jung HC
FAU - Kim, Noe Kyeong
AU  - Kim NK
FAU - Bang, Yung-Jue
AU  - Bang YJ
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Clin Cancer Res
JID - 9502500
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lymphokines)
RN  - 0 (Plasmids)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 63231-63-0 (RNA)
RN  - 7782-44-7 (Oxygen)
RN  - EC 1.13.12.- (Luciferase)
RN  - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase)
SB  - IM
MH  - 1-Phosphatidylinositol 3-Kinase/metabolism
MH  - Anoxia
MH  - Dose-Response Relationship, Drug
MH  - Endothelial Growth Factors/metabolism
MH  - Genes, Reporter
MH  - Human
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - Intercellular Signaling Peptides and Proteins/metabolism
MH  - Luciferase/metabolism
MH  - Lymphokines/metabolism
MH  - Oxygen/*metabolism
MH  - Plasmids/metabolism
MH  - Promoter Regions (Genetics)
MH  - RNA/metabolism
MH  - *Reactive Oxygen Species
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Stomach Neoplasms/*metabolism
MH  - Support, Non-U.S. Gov't
MH  - Time Factors
MH  - Trans-Activation (Genetics)
MH  - Transcription Factors/*metabolism
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2003/01/23 04:00
MHDA- 2003/07/18 05:00
PST - ppublish
SO  - Clin Cancer Res 2003 Jan;9(1):433-40.

PMID- 12368217
OWN - NLM
STAT- completed
DA  - 20021007
DCOM- 20021105
LR  - 20031114
IS  - 0002-9440
VI  - 161
IP  - 4
DP  - 2002 Oct
TI  - Esophageal ulceration triggers expression of hypoxia-inducible factor-1
      alpha and activates vascular endothelial growth factor gene: implications
      for angiogenesis and ulcer healing.
PG  - 1449-57
AB  - Our previous studies demonstrated that enhanced epithelial cell
      proliferation is important for healing of experimental esophageal ulcers.
      However, the roles of angiogenesis, its major mediator, vascular
      endothelial growth factor (VEGF), and the mechanism(s) regulating VEGF
      expression during esophageal ulcer healing remain unknown. Esophageal
      ulcers were induced in rats by focal application of acetic acid. We
      studied expressions of hypoxia-inducible transcription factor-1 alpha
      (HIF-1 alpha), an activator of the VEGF gene, and VEGF by reverse
      transcriptase-polymerase chain reaction, Western blotting, and
      immunostaining. To determine the efficacy of VEGF gene therapy in
      esophageal ulcer healing, we studied whether a single local injection of
      plasmid cDNA encoding recombinant human VEGF(165) affects ulcer healing
      and angiogenesis. Esophageal ulceration induced HIF-1 alpha protein
      expression and VEGF gene activation reflected by increased VEGF mRNA
      (240%) and VEGF protein (310%) levels. HIF-1 alpha protein was expressed
      in microvessels bordering necrosis where it co-localized with VEGF.
      Injection of cDNA encoding VEGF(165) significantly enhanced angiogenesis
      and accelerated esophageal ulcer healing. These results: 1) suggest that
      HIF-1 alpha may mediate esophageal ulceration-triggered VEGF gene
      activation, 2) indicate an essential role of VEGF and angiogenesis in
      esophageal ulcer healing, and 3) demonstrate the feasibility of gene
      therapy for the treatment of esophageal ulcers.
AD  - Department of Medicine, VA Medical Center, Long Beach, California 90822,
      USA.
FAU - Baatar, Dolgor
AU  - Baatar D
FAU - Jones, Michael K
AU  - Jones MK
FAU - Tsugawa, Koji
AU  - Tsugawa K
FAU - Pai, Rama
AU  - Pai R
FAU - Moon, Woo S
AU  - Moon WS
FAU - Koh, Gou Y
AU  - Koh GY
FAU - Kim, Injune
AU  - Kim I
FAU - Kitano, Seigo
AU  - Kitano S
FAU - Tarnawski, Andrzej S
AU  - Tarnawski AS
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Am J Pathol
JID - 0370502
RN  - 0 (DNA Primers)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lymphokines)
RN  - 0 (Plasmids)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 0 (vascular endothelial growth factor A, human)
SB  - AIM
SB  - IM
CIN - Am J Pathol. 2002 Oct;161(4):1101-5. PMID: 12368182
MH  - Animals
MH  - Base Sequence
MH  - DNA Primers
MH  - Disease Models, Animal
MH  - Endothelial Growth Factors/*genetics
MH  - Esophageal Diseases/*genetics/pathology
MH  - Esophagus/*blood supply
MH  - *Gene Expression Regulation
MH  - Intercellular Signaling Peptides and Proteins/*genetics
MH  - Lymphokines/*genetics
MH  - Male
MH  - Neovascularization, Pathologic
MH  - Plasmids
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Stomach Ulcer/*genetics/pathology
MH  - Support, Non-U.S. Gov't
MH  - Support, U.S. Gov't, Non-P.H.S.
MH  - Transcription Factors/*genetics
MH  - Transcription, Genetic
MH  - Translation, Genetic
MH  - Ulcer/genetics/pathology
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
MH  - Wound Healing/genetics/*physiology
EDAT- 2002/10/09 04:00
MHDA- 2002/11/26 04:00
PST - ppublish
SO  - Am J Pathol 2002 Oct;161(4):1449-57.

PMID- 12208766
OWN - NLM
STAT- completed
DA  - 20020904
DCOM- 20021003
LR  - 20040818
IS  - 0008-5472
VI  - 62
IP  - 17
DP  - 2002 Sep 1
TI  - The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor
      1alpha protein expression: Trx-1 overexpression results in increased
      vascular endothelial growth factor production and enhanced tumor
      angiogenesis.
PG  - 5089-95
AB  - Hypoxia-inducible factor 1 (HIF-1), a heterodimer of HIF-1alpha and
      HIF-1beta subunits, is a transcriptional activator central to the cellular
      response to low oxygen that includes metabolic adaptation, angiogenesis,
      metastasis, and inhibited apoptosis. Thioredoxin-1 (Trx-1) is a small
      redox protein overexpressed in a number of human primary tumors. We have
      examined the effects of Trx-1 on HIF activity and the activation of
      downstream genes. Stable transfection of human breast carcinoma MCF-7
      cells with human Trx-1 caused a significant increase in HIF-1alpha protein
      levels under both normoxic (20% oxygen) and hypoxic (1% oxygen)
      conditions. Trx-1 increased hypoxia-induced HIF-1 transactivation activity
      measured using a luciferase reporter under the control of the hypoxia
      response element. Changes in HIF-1alpha mRNA levels did not account for
      the changes observed at the protein level, and HIF-1beta protein levels
      did not change. Trx-1 transfection also caused a significant increase in
      the protein products of hypoxia-responsive genes, including vascular
      endothelial growth factor (VEGF) and nitric oxide synthase 2 in a number
      of different cell lines (MCF-7 human breast and HT29 human colon
      carcinomas and WEHI7.2 mouse lymphoma cells) under both normoxic and
      hypoxic conditions. The pattern of expression of the different isoforms of
      VEGF was not changed by Trx-1. Transfection of a redox-inactive Trx-1
      (C32S/C35S) markedly decreased levels of HIF-1alpha protein, HIF-1
      transactivating activity, and VEGF protein in MCF-7 cells compared with
      empty vector controls. In vivo studies using WEHI7.2 cells transfected
      with Trx-1 showed significantly increased tumor VEGF and angiogenesis. The
      results suggest that Trx-1 increases HIF-1alpha protein levels in cancer
      cells and increases VEGF production and tumor angiogenesis.
AD  - Arizona Cancer Center, University of Arizona, Tucson, Arizona, 85724-5024,
      USA. swelsh@azcc.arizona.edu
FAU - Welsh, Sarah J
AU  - Welsh SJ
FAU - Bellamy, William T
AU  - Bellamy WT
FAU - Briehl, Margaret M
AU  - Briehl MM
FAU - Powis, Garth
AU  - Powis G
LA  - eng
GR  - CA17094/CA/NCI
GR  - CA77204/CA/NCI
GR  - CA78277/CA/NCI
GR  - CA90821/CA/NCI
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JID - 2984705R
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Lymphokines)
RN  - 0 (Membrane Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (TRX1 protein, S cerevisiae)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 138391-32-9 (Arnt protein)
RN  - 52500-60-4 (Thioredoxin)
RN  - EC 1.14.13.- (inducible nitric oxide synthase)
RN  - EC 1.14.13.39 (Nitric-Oxide Synthase)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/*blood supply/genetics/metabolism
MH  - Cell Hypoxia/physiology
MH  - Colonic Neoplasms/*blood supply/genetics/metabolism
MH  - Endothelial Growth Factors/*biosynthesis/genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Human
MH  - Lymphokines/*biosynthesis/genetics
MH  - Lymphoma/genetics/metabolism
MH  - Membrane Proteins/biosynthesis/pharmacology/*physiology
MH  - Mice
MH  - Neovascularization, Pathologic/genetics/*metabolism/pathology
MH  - Nitric-Oxide Synthase/biosynthesis
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Support, U.S. Gov't, P.H.S.
MH  - Thioredoxin/biosynthesis/pharmacology
MH  - Trans-Activation (Genetics)
MH  - Transcription Factors/*biosynthesis/genetics
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2002/09/05 10:00
MHDA- 2002/10/04 04:00
PST - ppublish
SO  - Cancer Res 2002 Sep 1;62(17):5089-95.

PMID- 12149254
OWN - NLM
STAT- completed
DA  - 20021007
DCOM- 20021125
LR  - 20040818
IS  - 0021-9258
VI  - 277
IP  - 41
DP  - 2002 Oct 11
TI  - Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated
      vascular endothelial growth factor expression, which is dependent on MAP
      kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells.
PG  - 38205-11
AB  - Stimulation of human colon cancer cells with insulin-like growth factor 1
      (IGF-1) induces expression of the VEGF gene, encoding vascular endothelial
      growth factor. In this article we demonstrate that exposure of HCT116
      human colon carcinoma cells to IGF-1 induces the expression of HIF-1
      alpha, the regulated subunit of hypoxia-inducible factor 1, a known
      transactivator of the VEGF gene. In contrast to hypoxia, which induces
      HIF-1 alpha expression by inhibiting its ubiquitination and degradation,
      IGF-1 did not inhibit these processes, indicating an effect on HIF-1 alpha
      protein synthesis. IGF-1 stimulation of HIF-1 alpha protein and VEGF mRNA
      expression was inhibited by treating cells with inhibitors of
      phosphatidylinositol 3-kinase and MAP kinase signaling pathways. These
      inhibitors also blocked the IGF-1-induced phosphorylation of the
      translational regulatory proteins 4E-BP1, p70 S6 kinase, and eIF-4E, thus
      providing a mechanism for the modulation of HIF-1 alpha protein synthesis.
      Forced expression of a constitutively active form of the MAP kinase
      kinase, MEK2, was sufficient to induce HIF-1 alpha protein and VEGF mRNA
      expression. Involvement of the MAP kinase pathway represents a novel
      mechanism for the induction of HIF-1 alpha protein expression in human
      cancer cells.
AD  - McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins
      University School of Medicine, Baltimore, Maryland 21287, USA.
FAU - Fukuda, Ryo
AU  - Fukuda R
FAU - Hirota, Kiichi
AU  - Hirota K
FAU - Fan, Fan
AU  - Fan F
FAU - Jung, Young Do
AU  - Jung YD
FAU - Ellis, Lee M
AU  - Ellis LM
FAU - Semenza, Gregg L
AU  - Semenza GL
LA  - eng
GR  - R01-CA74821/CA/NCI
GR  - R01-DK39869/DK/NIDDK
PT  - Journal Article
DEP - 20020730
PL  - United States
TA  - J Biol Chem
JID - 2985121R
RN  - 0 (Carrier Proteins)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lymphokines)
RN  - 0 (MAP Kinase Signaling System)
RN  - 0 (PHAS-I protein)
RN  - 0 (Phosphoproteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Ubiquitin)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.1.- (MAP kinase kinase 2)
RN  - EC 2.7.1.112 (Protein-Tyrosine Kinase)
RN  - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.1.37 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 2.7.1.37 (Ribosomal Protein S6 Kinases, 70kD)
SB  - IM
MH  - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/*metabolism
MH  - Animals
MH  - Anoxia/metabolism
MH  - Carcinoma/*metabolism
MH  - Carrier Proteins/metabolism
MH  - Colonic Neoplasms/*metabolism
MH  - Endothelial Growth Factors/genetics/*metabolism
MH  - Enzyme Inhibitors/metabolism
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Gene Expression Regulation
MH  - Human
MH  - Insulin-Like Growth Factor I/*metabolism
MH  - Intercellular Signaling Peptides and Proteins/genetics/*metabolism
MH  - Lymphokines/genetics/*metabolism
MH  - MAP Kinase Signaling System/*physiology
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Phosphoproteins/metabolism
MH  - Protein-Tyrosine Kinase/metabolism
MH  - Repressor Proteins/metabolism
MH  - Ribosomal Protein S6 Kinases, 70kD/metabolism
MH  - Support, U.S. Gov't, P.H.S.
MH  - Transcription Factors/genetics/*metabolism
MH  - Ubiquitin/metabolism
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2002/08/01 10:00
MHDA- 2002/11/26 04:00
PHST- 2002/Jul/30 [aheadofprint]
AID - 10.1074/jbc.M203781200 [doi]
AID - M203781200 [pii]
PST - ppublish
SO  - J Biol Chem 2002 Oct 11;277(41):38205-11. Epub 2002 Jul 30.

PMID- 12016145
OWN - NLM
STAT- completed
DA  - 20020517
DCOM- 20020621
LR  - 20031114
IS  - 0143-3334
VI  - 23
IP  - 5
DP  - 2002 May
TI  - Modulation of angiogenesis-related proteins synthesis by sodium butyrate
      in colon cancer cell line HT29.
PG  - 735-40
AB  - Sodium butyrate (NaB), a short-chain fatty acid naturally present in the
      human colon, is able to induce cell cycle arrest, differentiation and
      apoptosis in colon cancer cells. In addition to these effects, we
      investigated the effect of NaB on two angiogenesis-related proteins in a
      colon carcinoma cell line (HT29): vascular endothelial growth factor
      (VEGF), the most potent angiogenic factor, and hypoxia-inducible factor
      (HIF)-1alpha, the main transcription activator of the VEGF gene, which are
      both constitutively expressed at high levels in HT29 also in normoxic
      conditions. NaB treatment had a different effect on VEGF165 and HIF-1alpha
      expression. In fact, it induced a dose-dependent down regulation of the
      VEGF165 protein level that was not paralleled by a concomitant down
      regulation of the corresponding mRNA, suggesting a post-translational
      regulation of the factor. Conversely, after 24 h of treatment all the
      tested NaB concentrations reduced the HIF-1alpha protein level, whereas
      after a longer time of exposure HIF-1alpha level increased in the presence
      of a high NaB concentration (2 mM) with a concomitant increase in
      HIF-1alpha mRNA. These results indicate that NaB, besides regulating other
      fundamental cellular processes, is able to modulate the expression of two
      important angiogenesis-related molecules and suggested a further possible
      clinical application of this short-chain fatty acid as an anti-angiogenic
      compound in association with conventional chemotherapeutic agents.
AD  - Department of Experimental Oncology, Determinants of Prognosis and
      Treatment Response Unit, Istituto Nazionale per lo Studio e la Cura dei
      Tumori, Milan, Italy.
FAU - Pellizzaro, Cinzia
AU  - Pellizzaro C
FAU - Coradini, Danila
AU  - Coradini D
FAU - Daidone, Maria Grazia
AU  - Daidone MG
LA  - eng
PT  - Journal Article
PL  - England
TA  - Carcinogenesis
JID - 8008055
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Lymphokines)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 0 (vascular endothelial growth factor A, human)
RN  - 107-92-6 (Butyric Acid)
SB  - IM
MH  - Butyric Acid/*pharmacology
MH  - Colonic Neoplasms/*metabolism/pathology
MH  - Endothelial Growth Factors/*biosynthesis/metabolism
MH  - HT29 Cells
MH  - Human
MH  - Lymphokines/*biosynthesis/metabolism
MH  - *Neovascularization, Pathologic
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Support, Non-U.S. Gov't
MH  - Transcription Factors/*biosynthesis/metabolism
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2002/05/23 10:00
MHDA- 2002/06/22 10:01
PST - ppublish
SO  - Carcinogenesis 2002 May;23(5):735-40.

PMID- 11933073
OWN - NLM
STAT- completed
DA  - 20020404
DCOM- 20020509
IS  - 0899-1987
VI  - 33
IP  - 4
DP  - 2002 Apr
TI  - Quinoxaline 1,4-dioxides: hypoxia-selective therapeutic agents.
PG  - 198-205
AB  - A problem that confronts clinicians in the treatment of cancer is the
      resistance of hypoxic tumors to chemotherapy and radiation therapy. Thus,
      the development of new drugs that are toxic to hypoxic cells found in
      solid tumors is an important objective for effective anticancer
      chemotherapy. We recently showed that the heterocyclic aromatic N-oxides,
      quinoxaline 1,4-dioxides (QdNOs), are cytotoxic to tumor cells cultured
      under hypoxia. In this study, we evaluated the hypoxia-selective toxicity
      of four diversely substituted QdNOs and determined their effect on the
      expression of hypoxia inducible factor (HIF) 1alpha in the human colon
      cancer cell line T-84. The various QdNOs were found to possess a 50- to
      100-fold greater cytotoxicity to T-84 cells cultured under hypoxia
      compared with oxia. Interestingly, the hypoxia cytotoxicity ratio (HCR),
      the ratio of equitoxic concentrations of the drug under aerobic/anoxic
      conditions, was highly structure related and depended on the nature of the
      substituents on the QdNO heterocycle. The most cytotoxic
      2-benzoyl-3-phenyl-6,7-dichloro derivative of QdNO (DCQ) was potent at a
      dose of 1 microM with an HCR of 100 and significantly reduced the levels
      of HIF-1alpha transcript and protein. The 2-benzoyl-3-phenyl derivative
      (BPQ) had a hypoxia potency of 20 microM and an HCR of 40. By contrast,
      the 2-aceto-3-methyl and the 2,3-tetramethylene (TMQ) derivatives of QdNO
      were much less cytotoxic under hypoxia (HCRs of 8.5 and 6.5, respectively)
      and reduced the expression of HIF-1alpha mRNA to a much lesser extent.
      Because the nonchlorinated analogue BPQ did not demonstrate behavior
      similar to that of DCQ, we hypothesize that the C-6, C-7-chlorine of DCQ
      might play a significant role in the selective hypoxic cytotoxicity of the
      drug.
CI  - Copyright 2002 Wiley-Liss, Inc.
AD  - Department of Biology, American University of Beirut, Beirut, Lebanon.
FAU - Diab-Assef, Mona
AU  - Diab-Assef M
FAU - Haddadin, Makhluf J
AU  - Haddadin MJ
FAU - Yared, Pierre
AU  - Yared P
FAU - Assaad, Chafika
AU  - Assaad C
FAU - Gali-Muhtasib, Hala U
AU  - Gali-Muhtasib HU
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Mol Carcinog
JID - 8811105
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinoxalines)
RN  - 2423-66-7 (quindoxin)
SB  - IM
MH  - Aerobiosis
MH  - Antineoplastic Agents/toxicity
MH  - Cell Hypoxia/*drug effects
MH  - Cell Survival/drug effects
MH  - Colonic Neoplasms
MH  - Dose-Response Relationship, Drug
MH  - Human
MH  - Kinetics
MH  - Quinoxalines/*toxicity
MH  - Structure-Activity Relationship
MH  - Support, Non-U.S. Gov't
MH  - Tumor Cells, Cultured
EDAT- 2002/04/05 10:00
MHDA- 2002/05/10 10:01
AID - 10.1002/mc.10036 [pii]
PST - ppublish
SO  - Mol Carcinog 2002 Apr;33(4):198-205.

PMID- 11923216
OWN - NLM
STAT- completed
DA  - 20020429
DCOM- 20020506
LR  - 20031114
IS  - 1530-6860
VI  - 16
IP  - 7
DP  - 2002 May
TI  - Apoptosis in hypoxic human pancreatic islets correlates with HIF-1alpha
      expression.
PG  - 745-7
AB  - To become insulin independent, patients with type 1 diabetes mellitus
      require transplantation of at least two donor pancreata because of massive
      beta-cell loss in the early post-transplantation period. Many studies
      describing the introduction of new immunosuppressive protocols have shown
      that this loss is due to not only immunological events but also
      nonimmunological factors. To test to what extent hypoxia may contribute to
      early graft loss, we analyzed the occurrence of apoptotic events and the
      expression of hypoxia-inducible factor 1 (HIF-1), a heterodimeric
      transcription factor consisting of an oxygen-dependent alpha subunit and a
      constitutive beta subunit. Histological analysis of human and rat islets
      revealed nuclear pyknosis as early as 6 h after hypoxic exposure (1% O2).
      Moreover, immunoreactivity to activated caspase-3 was observed in the core
      region of isolated human islets. Of note, both of these markers of
      apoptosis topographically overlap with HIF-1alpha immunoreactivity.
      HIF-1alpha mRNA was detected in islets from human and rat as well as in
      several murine beta-cell lines. When exposed to hypoxia, mouse insulinoma
      cells (MIN6) had an increased HIF-1alpha protein level, whereas its mRNA
      level did not alter. In conclusion, our data provide convincing evidence
      that reduced oxygenation is an important cause of beta-cell loss and
      suggest that HIF-1alpha protein level is an indicator for hypoxic regions
      undergoing apoptotic cell death. These observations suggest that gene
      expression under the control of HIF-1 represents a potential therapeutic
      tool for improving engraftment of transplanted islets.
AD  - Clinic for Visceral and Transplant Surgery, University Hospital Zurich,
      CH-8091 Zurich, Switzerland.
FAU - Moritz, Wolfgang
AU  - Moritz W
FAU - Meier, Franziska
AU  - Meier F
FAU - Stroka, Deborah M
AU  - Stroka DM
FAU - Giuliani, Mauro
AU  - Giuliani M
FAU - Kugelmeier, Patrick
AU  - Kugelmeier P
FAU - Nett, Philipp C
AU  - Nett PC
FAU - Lehmann, Roger
AU  - Lehmann R
FAU - Candinas, Daniel
AU  - Candinas D
FAU - Gassmann, Max
AU  - Gassmann M
FAU - Weber, Markus
AU  - Weber M
LA  - eng
PT  - Journal Article
DEP - 20020326
PL  - United States
TA  - FASEB J
JID - 8804484
RN  - 0 (HIF1alpha protein)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Active Transport, Cell Nucleus
MH  - Animals
MH  - *Apoptosis
MH  - Cell Hypoxia
MH  - Cell Line
MH  - Cell Nucleus/metabolism
MH  - Cells, Cultured
MH  - Human
MH  - Islets of Langerhans/*cytology/*metabolism
MH  - Models, Biological
MH  - Rats
MH  - Trans-Activation (Genetics)
MH  - Transcription Factors/*biosynthesis/genetics/metabolism
MH  - Up-Regulation
EDAT- 2002/03/30 10:00
MHDA- 2002/05/07 10:01
PHST- 2002/Mar/26 [aheadofprint]
AID - 10.1096/fj.01-0403fje [doi]
AID - 01-0403fje [pii]
PST - ppublish
SO  - FASEB J 2002 May;16(7):745-7. Epub 2002 Mar 26.

PMID- 11772947
OWN - NLM
STAT- completed
DA  - 20020130
DCOM- 20020403
LR  - 20040520
IS  - 1530-6860
VI  - 16
IP  - 2
DP  - 2002 Feb
TI  - von Hippel Lindau tumor suppressor and HIF-1alpha: new targets of NSAIDs
      inhibition of hypoxia-induced angiogenesis.
PG  - 264-6
AB  - Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin
      synthesis and impair healing of gastrointestinal ulcers and growth of
      colonic tumors, in part, by inhibiting angiogenesis. The mechanisms of
      this inhibition are incompletely explained. Here we demonstrate that both
      nonselective (indomethacin) and COX-2-selective (NS-398) NSAIDs inhibit
      hypoxia-induced in vitro angiogenesis in gastric microvascular endothelial
      cells via coordinated sequential events: 1) increased expression of the
      von Hippel-Lindau (VHL) tumor suppressor, which targets proteins for
      ubiquitination leading to 2) reduced accumulation of hypoxia-inducible
      factor-1alpha (HIF-1alpha) and, as a result, 3) reduced expression of
      vascular endothelial growth factor (VEGF) and its specific receptor Flt-1.
      Because HIF-1alpha is the major trigger for hypoxia-induced activation of
      the VEGF and Flt-1 genes, this could explain how NSAIDs inhibit
      hypoxia-induced angiogenesis. Exogenous VEGF and, to a lesser extent,
      exogenous prostaglandins partly reversed the NSAIDs inhibition of
      hypoxia-induced angiogenesis. Taken together, these results indicate that
      NSAIDs inhibit hypoxia-induced angiogenesis in endothelial cells by
      inhibiting VEGF and Flt-1 expression through increased VHL expression and
      the resulting ubiquitination and degradation of HIF-1alpha. This action of
      NSAIDs has both prostaglandin-dependent and prostaglandin-independent
      components.
AD  - Department of Medicine, Veterans Affairs Medical Center, Long Beach,
      California 90822, USA.
FAU - Jones, Michael K
AU  - Jones MK
FAU - Szabo, Imre L
AU  - Szabo IL
FAU - Kawanaka, Hirofumi
AU  - Kawanaka H
FAU - Husain, Syeda S
AU  - Husain SS
FAU - Tarnawski, Andrzej S
AU  - Tarnawski AS
LA  - eng
PT  - Journal Article
DEP - 20011228
PL  - United States
TA  - FASEB J
JID - 8804484
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Lymphokines)
RN  - 0 (Nitrobenzenes)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sulfonamides)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Ubiquitin)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 123653-11-2 (N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide)
RN  - 53-86-1 (Indomethacin)
RN  - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.1.112 (Vascular Endothelial Growth Factor Receptor-1)
RN  - EC 6. (Ligases)
RN  - EC 6.3.2.19 (Ubiquitin-Protein Ligases)
RN  - EC 6.3.2.19 (VHL protein, human)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Cell Hypoxia/physiology
MH  - Cell Line
MH  - Endothelial Growth Factors/genetics/metabolism/pharmacology
MH  - Endothelium, Vascular/cytology/drug effects/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Human
MH  - Indomethacin/pharmacology
MH  - Ligases/*drug effects/genetics/metabolism
MH  - Lymphokines/drug effects/genetics/metabolism/pharmacology
MH  - Neovascularization, Pathologic/physiopathology/prevention & control
MH  - Nitrobenzenes/pharmacology
MH  - Proto-Oncogene Proteins/drug effects/genetics/metabolism
MH  - RNA, Messenger/drug effects/genetics/metabolism
MH  - Receptor Protein-Tyrosine Kinases/drug effects/genetics/metabolism
MH  - Sulfonamides/pharmacology
MH  - Transcription Factors/*drug effects/genetics/metabolism
MH  - *Tumor Suppressor Proteins
MH  - Ubiquitin/metabolism
MH  - *Ubiquitin-Protein Ligases
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factor Receptor-1
MH  - Vascular Endothelial Growth Factors
EDAT- 2002/01/05 10:00
MHDA- 2002/04/04 10:01
PHST- 2001/Dec/28 [aheadofprint]
AID - 10.1096/fj.01-0589fje [doi]
AID - 01-0589fje [pii]
PST - ppublish
SO  - FASEB J 2002 Feb;16(2):264-6. Epub 2001 Dec 28.

PMID- 11758829
OWN - NLM
STAT- completed
DA  - 20011207
DCOM- 20011228
LR  - 20031114
IS  - 0024-3205
VI  - 69
IP  - 25-26
DP  - 2001 Nov 9
TI  - Activation of hypoxia inducible factor-1alpha in gastric mucosa in
      response to ethanol injury: a trigger for angiogenesis?
PG  - 3035-44
AB  - Gastric mucosal injury triggers angiogenesis and activation of VEGF
      expression, but the mechanism(s) of VEGF gene activation are not known. In
      some tissues (e.g. myocardium), hypoxia triggers activation of
      hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor known
      to activate VEGF gene expression. This study was aimed to determine
      whether hypoxia and/or alcohol injury may induces HIF-1alpha in gastric
      mucosa. Normal rat gastric tissue was incubated in organ culture under
      either hypoxic or normoxic conditions for 6hrs. Rats received,
      intragastrically, either saline or alcohol and gastric mucosa bordering
      necrosis was obtained at 1-24hrs. HIF-1alpha mRNA and protein were
      determined by RT-PCR and Western-blot analysis. HIF-1alpha and VEGF
      proteins were localized by immunostaining. Incubation of normal gastric
      mucosa under hypoxia caused a significant elevation of HIF-1alpha mRNA
      (20+/-2%, p<0.05) and protein (262+/-15%, p<0.005) vs. normoxia. Following
      alcohol injury, gastric mucosa bordering necrosis demonstrated a
      significant increase in HIF-1alpha mRNA at 3 and 6hrs (40+/-4%, 19+/-2%;
      p<0.05), and protein (>300+/-16%; p<0.02 at all time points; highest at
      1-3hrs). HIF-1alpha signal was detected in regenerating mucosal
      microvessels, where it co-localized with VEGF. Since HIF-1alpha initiates
      transcription of VEGF mRNA, HIF-1alpha activation by ethanol-induced
      injury is likely responsible for activation of VEGF gene and induction of
      angiogenesis.
AD  - VA Medical Center, Long Beach, CA 90822, USA.
FAU - Szabo, I L
AU  - Szabo IL
FAU - Kawanaka, H
AU  - Kawanaka H
FAU - Jones, M K
AU  - Jones MK
FAU - Pai, R
AU  - Pai R
FAU - Soreghan, B A
AU  - Soreghan BA
FAU - Baatar, D
AU  - Baatar D
FAU - Husain, S S
AU  - Husain SS
FAU - Tarnawski, A S
AU  - Tarnawski AS
LA  - eng
PT  - Journal Article
PL  - England
TA  - Life Sci
JID - 0375521
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Lymphokines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 64-17-5 (Ethanol)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Hypoxia
MH  - Endothelial Growth Factors/analysis/biosynthesis/genetics
MH  - Ethanol/*toxicity
MH  - Gastric Mucosa/blood supply/*drug effects/metabolism
MH  - Immunohistochemistry
MH  - In Vitro
MH  - Lymphokines/analysis/biosynthesis/genetics
MH  - Male
MH  - Necrosis
MH  - Neovascularization, Pathologic/*metabolism
MH  - Organ Culture
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Regeneration
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Support, U.S. Gov't, Non-P.H.S.
MH  - Transcription Factors/analysis/genetics/*metabolism
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2002/01/05 10:00
MHDA- 2002/01/05 10:01
PST - ppublish
SO  - Life Sci 2001 Nov 9;69(25-26):3035-44.

PMID- 11535709
OWN - NLM
STAT- completed
DA  - 20010905
DCOM- 20011011
LR  - 20011102
IS  - 0027-8874
VI  - 93
IP  - 17
DP  - 2001 Sep 5
TI  - Transcriptional response to hypoxia in human tumors.
PG  - 1337-43
AB  - BACKGROUND: The presence of hypoxic regions within solid tumors is
      associated with a more malignant tumor phenotype and worse prognosis. To
      obtain a blood supply and protect against cellular damage and death,
      oxygen-deprived cells in tumors alter gene expression, resulting in
      resistance to therapy. To investigate the mechanisms by which cancer cells
      adapt to hypoxia, we looked for novel hypoxia-induced genes. METHODS: The
      transcriptional response to hypoxia in human glioblastoma cells was
      quantified with the use of serial analysis of gene expression. The time
      course of gene expression in response to hypoxia in a panel of various
      human tumor cell lines was measured by real-time polymerase chain
      reaction. Hypoxic regions of human carcinomas were chemically marked with
      pimonidazole. Immunohistochemistry and in situ hybridization were used to
      examine gene expression in the tumor's hypoxic regions. RESULTS: From the
      24 504 unique transcripts expressed, 10 new hypoxia-regulated genes were
      detected-all induced, to a greater extent than vascular endothelial growth
      factor, a hypoxia-induced mitogen that promotes blood vessel growth. These
      genes also responded to hypoxia in breast and colon cancer cells and were
      activated by hypoxia-inducible factor 1, a key regulator of hypoxic
      responses. In tumors, gene expression was limited to hypoxic regions.
      Induced genes included hexabrachion (an extracellular matrix
      glycoprotein), stanniocalcin 1 (a calcium homeostasis protein), and an
      angiopoietin-related gene. CONCLUSIONS: We have identified the genes that
      are transcriptionally activated within hypoxic malignant cells, a crucial
      first step in understanding the complex interactions driving hypoxia
      response. Within our catalogue of hypoxia-responsive genes are novel
      candidates for hypoxia-driven angiogenesis.
AD  - Department of Pathology, Duke University Medical Center, Durham, NC 27710,
      USA.
FAU - Lal, A
AU  - Lal A
FAU - Peters, H
AU  - Peters H
FAU - St  Croix, B
AU  - St  Croix B
FAU - Haroon, Z A
AU  - Haroon ZA
FAU - Dewhirst, M W
AU  - Dewhirst MW
FAU - Strausberg, R L
AU  - Strausberg RL
FAU - Kaanders, J H
AU  - Kaanders JH
FAU - van der Kogel, A J
AU  - van der Kogel AJ
FAU - Riggins, G J
AU  - Riggins GJ
LA  - eng
SI  - OMIM/601455
GR  - S98-146/PHS
PT  - Journal Article
PL  - United States
TA  - J Natl Cancer Inst
JID - 7503089
RN  - 0 (Glycoproteins)
RN  - 0 (Hormones)
RN  - 0 (Tenascin)
RN  - 76687-96-2 (teleocalcin)
SB  - IM
MH  - Blotting, Western
MH  - Cell Hypoxia/*genetics
MH  - *Gene Expression Regulation, Neoplastic
MH  - Glioblastoma/chemistry/*genetics
MH  - Glycoproteins/analysis/genetics
MH  - Hormones/analysis/genetics
MH  - Human
MH  - Immunohistochemistry
MH  - In Situ Hybridization
MH  - Neovascularization, Pathologic/genetics
MH  - Polymerase Chain Reaction/methods
MH  - Support, Non-U.S. Gov't
MH  - Support, U.S. Gov't, P.H.S.
MH  - Tenascin/analysis/genetics
MH  - Time Factors
MH  - *Transcription, Genetic
MH  - Tumor Cells, Cultured
MH  - Up-Regulation
EDAT- 2001/09/06 10:00
MHDA- 2001/10/12 10:01
PST - ppublish
SO  - J Natl Cancer Inst 2001 Sep 5;93(17):1337-43.

PMID- 11342587
OWN - NLM
STAT- completed
DA  - 20010508
DCOM- 20010628
LR  - 20031114
IS  - 0022-1007
VI  - 193
IP  - 9
DP  - 2001 May 7
TI  - Hypoxia-inducible factor 1-dependent induction of intestinal trefoil
      factor protects barrier function during hypoxia.
PG  - 1027-34
AB  - Mucosal organs such as the intestine are supported by a rich and complex
      underlying vasculature. For this reason, the intestine, and particularly
      barrier-protective epithelial cells, are susceptible to damage related to
      diminished blood flow and concomitant tissue hypoxia. We sought to
      identify compensatory mechanisms that protect epithelial barrier during
      episodes of intestinal hypoxia. Initial studies examining T84 colonic
      epithelial cells revealed that barrier function is uniquely resistant to
      changes elicited by hypoxia. A search for intestinal-specific,
      barrier-protective factors revealed that the human intestinal trefoil
      factor (ITF) gene promoter bears a previously unappreciated binding site
      for hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallel
      induction of ITF mRNA and protein. Electrophoretic mobility shift assay
      analysis using ITF-specific, HIF-1 consensus motifs resulted in a
      hypoxia-inducible DNA binding activity, and loading cells with antisense
      oligonucleotides directed against the alpha chain of HIF-1 resulted in a
      loss of ITF hypoxia inducibility. Moreover, addition of anti-ITF antibody
      resulted in a loss of barrier function in epithelial cells exposed to
      hypoxia, and the addition of recombinant human ITF to vascular endothelial
      cells partially protected endothelial cells from hypoxia-elicited barrier
      disruption. Extensions of these studies in vivo revealed prominent
      hypoxia-elicited increases in intestinal permeability in ITF null mice.
      HIF-1-dependent induction of ITF may provide an adaptive link for
      maintenance of barrier function during hypoxia.
AD  - Center for Experimental Therapeutics and Reperfusion Injury, Brigham and
      Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
FAU - Furuta, G T
AU  - Furuta GT
FAU - Turner, J R
AU  - Turner JR
FAU - Taylor, C T
AU  - Taylor CT
FAU - Hershberg, R M
AU  - Hershberg RM
FAU - Comerford, K
AU  - Comerford K
FAU - Narravula, S
AU  - Narravula S
FAU - Podolsky, D K
AU  - Podolsky DK
FAU - Colgan, S P
AU  - Colgan SP
LA  - eng
GR  - DK02503/DK/NIDDK
GR  - DK02564/DK/NIDDK
GR  - DK02682/DK/NIDDK
GR  - DK50189/DK/NIDDK
GR  - HL60569/HL/NHLBI
PT  - Journal Article
PL  - United States
TA  - J Exp Med
JID - 2985109R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Growth Substances)
RN  - 0 (HIF-1 protein)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Peptides)
RN  - 0 (Transcription Factors)
RN  - 146046-78-8 (trefoil factor)
SB  - IM
MH  - Animals
MH  - Caco-2 Cells
MH  - Cell Hypoxia
MH  - Cell Line
MH  - Colon/metabolism/physiology
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Dogs
MH  - Gene Expression
MH  - Growth Substances/*biosynthesis/genetics
MH  - Human
MH  - Intestinal Mucosa/metabolism/*physiology
MH  - Mice
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Peptides/genetics
MH  - Support, U.S. Gov't, P.H.S.
MH  - *Transcription Factors
EDAT- 2001/05/09 10:00
MHDA- 2001/06/29 10:01
PST - ppublish
SO  - J Exp Med 2001 May 7;193(9):1027-34.

PMID- 10934146
OWN - NLM
STAT- completed
DA  - 20000823
DCOM- 20000823
LR  - 20031114
IS  - 0002-9440
VI  - 157
IP  - 2
DP  - 2000 Aug
TI  - The expression and distribution of the hypoxia-inducible factors
      HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and
      tumor-associated macrophages.
PG  - 411-21
AB  - The cellular response to hypoxia includes the hypoxia-inducible factor-1
      (HIF-1)-induced transcription of genes involved in diverse processes such
      as glycolysis and angiogenesis. Induction of the HIF-regulated genes, as a
      consequence of the microenvironment or genetic changes, is known to have
      an important role in the growth of experimental tumors. Hypoxia-inducible
      factors 1alpha and 2alpha (HIF-1alpha and HIF-2alpha) are known to
      dimerize with the aryl hydrocarbon receptor nuclear translocator in
      mediating this response. Because regulation of the alpha chain protein
      level is a primary determinant of HIF activity, our aim was to investigate
      the distribution of HIF-1alpha and HIF-2alpha by immunohistochemistry in
      normal and pathological tissues using monoclonal antibodies (mAb). We
      raised a new mAb to detect HIF-1alpha, designated 122, and used our
      previously validated mAb 190b to HIF-2alpha. In the majority of solid
      tumors examined, including bladder, brain, breast, colon, ovarian,
      pancreatic, prostate, and renal carcinomas, nuclear expression of
      HIF-1alpha and -2alpha was observed in varying subsets of the tumor cells.
      HIF-2alpha was also strongly expressed by subsets of tumor-associated
      macrophages, sometimes in the absence of any tumor cell expression. Less
      frequently staining was observed in other stromal cells within the tumors
      and in normal tissue adjacent to tumor margins. In contrast, in normal
      tissue neither molecule was detectable except within subsets of bone
      marrow macrophages, where HIF-2alpha was strongly expressed.
AD  - Nuffield Department of Clinical Laboratory Sciences, University of Oxford,
      United Kingdom.
FAU - Talks, K L
AU  - Talks KL
FAU - Turley, H
AU  - Turley H
FAU - Gatter, K C
AU  - Gatter KC
FAU - Maxwell, P H
AU  - Maxwell PH
FAU - Pugh, C W
AU  - Pugh CW
FAU - Ratcliffe, P J
AU  - Ratcliffe PJ
FAU - Harris, A L
AU  - Harris AL
LA  - eng
PT  - Journal Article
PL  - UNITED STATES
TA  - Am J Pathol
JID - 0370502
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF-1 protein)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (bHLH-PAS factor HLF)
SB  - AIM
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - COS Cells
MH  - Cell Line
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Human
MH  - Immunohistochemistry
MH  - In Situ Hybridization
MH  - Macrophages/*chemistry/metabolism/pathology
MH  - Neoplasms/genetics/*metabolism/pathology
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Paraffin Embedding
MH  - RNA, Messenger/genetics/metabolism
MH  - Tissue Distribution
MH  - *Trans-Activators
MH  - *Transcription Factors
MH  - Tumor Cells, Cultured
EDAT- 2000/08/10 11:00
MHDA- 2000/08/29 11:01
PST - ppublish
SO  - Am J Pathol 2000 Aug;157(2):411-21.

PMID- 10678579
OWN - NLM
STAT- completed
DA  - 20000316
DCOM- 20000316
LR  - 20031114
IS  - 0091-7370
VI  - 30
IP  - 1
DP  - 2000 Jan
TI  - Molecular pathology of cyclooxygenase-2 in neoplasia.
PG  - 3-21
AB  - Cyclooxygenase (COX)-2 levels are elevated in several types of human
      cancer tissues. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs)
      inhibit both the COX-1 and COX-2 protein, the two enzymes that convert
      arachidonic acids to prostaglandins. Regular use of such NSAIDs
      significantly reduces the risk and spread of some cancers. The objective
      of this study was to elucidate the molecular pathology of neoplasms that
      overexpress COX-2. Epidemiological data and clinical studies were analyzed
      and compared with results of studies of human tumor tissues, animal
      models, and cultured tumor cells. COX-2, but not COX-1, is highly
      expressed in human colon carcinoma, squamous cell carcinoma of the
      esophagus, and skin cancer. COX-2 is inducible by oncogenes ras and scr,
      interleukin-1, hypoxia, benzo[a]pyrene, ultraviolet light, epidermal
      growth factor, transforming growth factor beta, and tumor necrosis factor
      alpha. Dexamethasone, antioxidants, and tumor-suppressor protein p53
      suppress COX-2 expression. COX-2 synthesizes prostaglandin E2 (PGE2) which
      stimulates bcl-2 and inhibits apoptosis, and induces interleukin-6 (IL-6)
      which enhances haptoglobin synthesis. PGE2 is associated with tumor
      metastases, IL-6 with cancer cell invasion, and haptoglobin with
      implantation and angiogenesis. Drastic reduction in polyp number results
      from COX-2 gene knockout as well as from selective COX-2 inhibition in a
      mouse model of human familial adenomatous polyposis. Nonselective NSAIDs,
      for instance aspirin, and selective COX-2 inhibitors such as celecoxib
      (SC-58635) and NS-398 suppress azoxymethane-induced colon carcinogenesis
      in rats. Aspirin, indomethacin, and ibuprofen decrease cultured lung
      cancer cell proliferation. Selective inhibition of COX-2 is preferable to
      nonselective inhibition. It reduces cancer cell proliferation, induces
      cancer cell apoptosis, and spares COX-1-induced cytoprotection of the
      gastrointestinal tract.
AD  - Department of Pathology, University of Illinois College of Medicine,
      Chicago 60612, USA. efosslie@uic.edu
FAU - Fosslien, E
AU  - Fosslien E
LA  - eng
PT  - Journal Article
PT  - Review
PT  - Review, Academic
PL  - UNITED STATES
TA  - Ann Clin Lab Sci
JID - 0410247
RN  - 0 (Isoenzymes)
RN  - EC 1.14.99.- (cyclooxygenase 2)
RN  - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthase)
SB  - IM
MH  - Animals
MH  - Carcinoma, Squamous Cell/*pathology
MH  - Colonic Neoplasms/*pathology
MH  - Esophageal Neoplasms/pathology
MH  - Gene Expression Regulation, Enzymologic
MH  - Gene Expression Regulation, Neoplastic
MH  - Human
MH  - Isoenzymes/*genetics/metabolism
MH  - Prostaglandin-Endoperoxide Synthase/*genetics/metabolism
MH  - Skin Neoplasms/*pathology
RF  - 160
EDAT- 2000/03/18
MHDA- 2000/03/18 00:01
PST - ppublish
SO  - Ann Clin Lab Sci 2000 Jan;30(1):3-21.

PMID- 10582706
OWN - NLM
STAT- completed
DA  - 19991214
DCOM- 19991214
LR  - 20031114
IS  - 0008-5472
VI  - 59
IP  - 22
DP  - 1999 Nov 15
TI  - Overexpression of hypoxia-inducible factor 1alpha in common human cancers
      and their metastases.
PG  - 5830-5
AB  - Neovascularization and increased glycolysis, two universal characteristics
      of solid tumors, represent adaptations to a hypoxic microenvironment that
      are correlated with tumor invasion, metastasis, and lethality.
      Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes
      encoding glucose transporters, glycolytic enzymes, and vascular
      endothelial growth factor. HIF-1 transcriptional activity is determined by
      regulated expression of the HIF-1alpha subunit. In this study, HIF-1alpha
      expression was analyzed by immunohistochemistry in 179 tumor specimens.
      HIF-1alpha was overexpressed in 13 of 19 tumor types compared with the
      respective normal tissues, including colon, breast, gastric, lung, skin,
      ovarian, pancreatic, prostate, and renal carcinomas. HIF-1alpha expression
      was correlated with aberrant p53 accumulation and cell proliferation.
      Preneoplastic lesions in breast, colon, and prostate overexpressed
      HIF-1alpha, whereas benign tumors in breast and uterus did not. HIF-1alpha
      overexpression was detected in only 29% of primary breast cancers but in
      69% of breast cancer metastases. In brain tumors, HIF-1alpha
      immunohistochemistry demarcated areas of angiogenesis. These results
      provide the first clinical data indicating that HIF-1alpha may play an
      important role in human cancer progression.
AD  - The Johns Hopkins Oncology Center, Brady Urological Institute, The Johns
      Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
FAU - Zhong, H
AU  - Zhong H
FAU - De Marzo, A M
AU  - De Marzo AM
FAU - Laughner, E
AU  - Laughner E
FAU - Lim, M
AU  - Lim M
FAU - Hilton, D A
AU  - Hilton DA
FAU - Zagzag, D
AU  - Zagzag D
FAU - Buechler, P
AU  - Buechler P
FAU - Isaacs, W B
AU  - Isaacs WB
FAU - Semenza, G L
AU  - Semenza GL
FAU - Simons, J W
AU  - Simons JW
LA  - eng
GR  - CA-58236/CA/NCI
GR  - R01-HL55338/HL/NHLBI
PT  - Journal Article
PL  - UNITED STATES
TA  - Cancer Res
JID - 2984705R
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF-1 protein)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Ki-67 Antigen)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Protein p53)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/metabolism
MH  - DNA-Binding Proteins/immunology/*metabolism
MH  - Disease Progression
MH  - Human
MH  - Ki-67 Antigen/metabolism
MH  - Mice
MH  - Neoplasm Proteins/*metabolism
MH  - Neoplasms/*metabolism
MH  - Nuclear Proteins/immunology/*metabolism
MH  - Protein p53/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - RNA, Messenger/metabolism
MH  - Reproducibility of Results
MH  - Support, Non-U.S. Gov't
MH  - Support, U.S. Gov't, Non-P.H.S.
MH  - Support, U.S. Gov't, P.H.S.
MH  - Transcription Factors/immunology/*metabolism
EDAT- 1999/12/03
MHDA- 1999/12/03 00:01
PST - ppublish
SO  - Cancer Res 1999 Nov 15;59(22):5830-5.

PMID- 10557090
OWN - NLM
STAT- completed
DA  - 19991203
DCOM- 19991203
LR  - 20020419
IS  - 0950-9232
VI  - 18
IP  - 44
DP  - 1999 Oct 28
TI  - Inhibition of cyclo-oxygenase 2 expression in colon cells by the
      chemopreventive agent curcumin involves inhibition of NF-kappaB activation
      via the NIK/IKK signalling complex.
PG  - 6013-20
AB  - Colorectal cancer is a major cause of cancer deaths in Western countries,
      but epidemiological data suggest that dietary modification might reduce
      these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of
      prostaglandin H synthase, which mediates prostaglandin synthesis during
      inflammation, and which is selectively overexpressed in colon tumours, is
      thought to play an important role in colon carcinogenesis. Curcumin, a
      constituent of turmeric, possesses potent anti-inflammatory activity and
      prevents colon cancer in animal models. However, its mechanism of action
      is not fully understood. We found that in human colon epithelial cells,
      curcumin inhibits COX2 induction by the colon tumour promoters, tumour
      necrosis factor alpha or fecapentaene-12. Induction of COX2 by
      inflammatory cytokines or hypoxia-induced oxidative stress can be mediated
      by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB
      activation, we examined whether its chemopreventive activity is related to
      modulation of the signalling pathway which regulates the stability of the
      NF-kappaB-sequestering protein, IkappaB. Recently components of this
      pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta,
      which phosphorylate IkappaB to release NF-kappaB, have been characterised.
      Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of
      the IKKs. This property, together with a long history of consumption
      without adverse health effects, makes curcumin an important candidate for
      consideration in colon cancer prevention.
AD  - MRC Toxicology Unit, University of Leicester, Leicester, LE1 9HN, UK.
FAU - Plummer, S M
AU  - Plummer SM
FAU - Holloway, K A
AU  - Holloway KA
FAU - Manson, M M
AU  - Manson MM
FAU - Munks, R J
AU  - Munks RJ
FAU - Kaptein, A
AU  - Kaptein A
FAU - Farrow, S
AU  - Farrow S
FAU - Howells, L
AU  - Howells L
LA  - eng
PT  - Journal Article
PL  - ENGLAND
TA  - Oncogene
JID - 8711562
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Caffeic Acids)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (I-kappa B)
RN  - 0 (Isoenzymes)
RN  - 0 (NF-kappa B)
RN  - 0 (Polyenes)
RN  - 0 (Tumor Necrosis Factor)
RN  - 104594-70-9 (caffeic acid phenethyl ester)
RN  - 16561-29-8 (Tetradecanoylphorbol Acetate)
RN  - 458-37-7 (Curcumin)
RN  - 60-12-8 (Phenylethyl Alcohol)
RN  - 84000-59-9 (1-(1-glycero)dodeca-1,3,5,7,9-pentaene)
RN  - EC 1.14.99.- (cyclooxygenase 2)
RN  - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthase)
RN  - EC 2.7.1.- (I kappa B kinase)
RN  - EC 2.7.1.- (NF-kappa B kinase)
RN  - EC 2.7.1.37 (Protein-Serine-Threonine Kinases)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Caffeic Acids/pharmacology
MH  - Colonic Neoplasms/*drug therapy/*metabolism
MH  - Curcumin/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/*pharmacology
MH  - Human
MH  - I-kappa B/drug effects/metabolism
MH  - Isoenzymes/drug effects/*metabolism
MH  - NF-kappa B/*drug effects/genetics/metabolism
MH  - Phenylethyl Alcohol/analogs & derivatives/pharmacology
MH  - Polyenes/pharmacology
MH  - Prostaglandin-Endoperoxide Synthase/drug effects/*metabolism
MH  - Protein-Serine-Threonine Kinases/drug effects/metabolism
MH  - Signal Transduction
MH  - Support, Non-U.S. Gov't
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Tumor Necrosis Factor/pharmacology
EDAT- 1999/11/11
MHDA- 1999/11/11 00:01
AID - 10.1038/sj.onc.1202980 [doi]
PST - ppublish
SO  - Oncogene 1999 Oct 28;18(44):6013-20.

PMID- 9558407
OWN - NLM
STAT- completed
DA  - 19980521
DCOM- 19980521
LR  - 20031114
IS  - 0006-4971
VI  - 91
IP  - 9
DP  - 1998 May 1
TI  - Mouse hypoxia-inducible factor-1alpha is encoded by two different mRNA
      isoforms: expression from a tissue-specific and a housekeeping-type
      promoter.
PG  - 3471-80
AB  - Hypoxic induction of erythropoietin (Epo) and other oxygen-dependent genes
      is mediated by the hypoxia-inducible factor-1 (HIF-1), a heterodimeric
      transactivator consisting of an alpha and a beta subunit. We previously
      found that the mouse gene encoding HIF-1alpha harbors two alternative
      first exons (I.1 and I.2), giving rise to two different HIF-1alpha mRNA
      isoforms. Here, we show by RNase protection analysis that the exon
      I.1-derived mRNA isoform is differentially expressed in mouse tissues,
      being highest in kidney, tongue, stomach, and testis, but undetectable in
      liver, whereas the exon I.2 mRNA isoform is ubiquitously expressed.
      Sequence and methylation analysis showed that, in contrast to exon I.1,
      exon I.2 resides within a region showing typical features of a CpG island,
      known to be associated with the 5' end of housekeeping genes. We
      identified a 232-bp minimal exon I.2 promoter that strongly induced
      reporter gene expression in mouse L929 fibroblasts and Hepa1 hepatoma
      cells. In contrast to L929 cells, the exon I.1 promoter was inactive in
      Hepa1 cells and hypoxic exposure (1% O2) markedly reduced exon I.2
      promoter activity in Hepa1 cells. Prolonged exposure of mice to hypoxia
      (7.5% O2 for up to 72 hours) also caused a decrease in liver HIF-1alpha
      mRNA, whereas aldolase mRNA levels increased. These findings might be
      related to the relatively low Epo levels in the adult liver.
AD  - Institute of Physiology, University of Zurich-Irchel, Zurich, Switzerland.
FAU - Wenger, R H
AU  - Wenger RH
FAU - Rolfs, A
AU  - Rolfs A
FAU - Spielmann, P
AU  - Spielmann P
FAU - Zimmermann, D R
AU  - Zimmermann DR
FAU - Gassmann, M
AU  - Gassmann M
LA  - eng
SI  - GENBANK/Y13656
PT  - Journal Article
PL  - UNITED STATES
TA  - Blood
JID - 7603509
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF-1 protein)
RN  - 0 (HIF1alpha protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
SB  - AIM
SB  - IM
MH  - Alternative Splicing
MH  - Animals
MH  - Anoxia/*genetics
MH  - Base Sequence
MH  - DNA Methylation
MH  - DNA-Binding Proteins/*genetics
MH  - Exons
MH  - Gene Expression Regulation
MH  - Mice
MH  - Molecular Sequence Data
MH  - Nuclear Proteins/*genetics
MH  - Promoter Regions (Genetics)
MH  - RNA, Messenger/genetics
MH  - Support, Non-U.S. Gov't
MH  - Tissue Distribution
MH  - Transcription Factors/genetics
EDAT- 1998/05/23
MHDA- 1998/05/23 00:01
PST - ppublish
SO  - Blood 1998 May 1;91(9):3471-80.

