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Targeting the hypoxia-inducible factor (HIF) pathway in cancer

  • Evon Poon (a1), Adrian L. Harris (a2) and Margaret Ashcroft (a1)

The central component of hypoxia sensing in the cell is the hypoxia-inducible factor (HIF) transcriptional complex. HIF activity is deregulated in many human cancers, especially those that are highly hypoxic. Hypoxic tumour cells are usually resistant to radiotherapy and most conventional chemotherapeutic agents, rendering them highly aggressive and metastatic. Overexpression of HIF-α, the regulatory subunit of HIF, is associated with increased vascular density, severity of tumour grade, treatment failure and a poor prognostic outcome with conventional therapies. Therefore HIF is an attractive, although challenging, therapeutic target, and several different strategies have been developed to target HIF directly or indirectly in recent years. This review outlines the preclinical and clinical advances in this arena and discusses which cancers may benefit from HIF-targeted therapy.

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*Corresponding author: Margaret Ashcroft, Centre for Cell Signalling and Molecular Genetics, University College London, Division of Medicine, Rayne Building, 5 University Street, London, WC1E 6JJ, UK. Tel: +44 (0)20 7679 6205; Fax: +44 (0)20 7679 6211; E-mail:
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1 P. Vaupel , M. Hockel and A. Mayer (2007) Detection and characterization of tumor hypoxia using pO2 histography. Antioxidants and Redox Signalling 9, 1221-1235

2 M. Hockel (1993) Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiotherapy and Oncology 26, 45-50

5 M. Hockel and P. Vaupel (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. Journal of the National Cancer Institute 93, 266-276

6 M. Hockel (1993) Tumor oxygenation: a new predictive parameter in locally advanced cancer of the uterine cervix. Gynecologic Oncology 51, 141-149

7 G.L. Wang (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the United States of America 92, 5510-5514

8 K. Guillemin and M.A. Krasnow (1997) The hypoxic response: huffing and HIFing. Cell 89, 9-12

9 G.L. Semenza (2003) Targeting HIF-1 for cancer therapy. Nature Reviews Cancer 3, 721-732

10 R. Bos (2001) Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. Journal of the National Cancer Institute 93, 309-314

12 P.H. Maxwell (1997) Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proceedings of the National Academy of Sciences of the United States of America 94, 8104-8109

13 A. Staab (2007) Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells. BMC Cancer 7, 213

14 K.J. Williams (2005) Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1. Radiotherapy and Oncology 75, 89-98

15 B.J. Moeller (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5, 429-441

16 B.J. Moeller (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8, 99-110

17 B.H. Jiang (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. Journal of Biological Chemistry 271, 17771-17778

19 R. Fukuda (2002) 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. Journal of Biological Chemistry 277, 38205-38211

20 E. Laughner (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Molecular and Cellular Biology 21, 3995-4004

21 L.E. Huang (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proceedings of the National Academy of Sciences of the United States of America 95, 7987-7992

22 M. Ivan (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464-468

23 P. Jaakkola (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468-472

24 N. Masson (2001) Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO Journal 20, 5197-5206

25 F. Yu (2001) HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proceedings of the National Academy of Sciences of the United States of America 98, 9630-9635

26 R.K. Bruick and S.L. McKnight (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337-1340

27 A.C. Epstein (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43-54

28 E. Berra (2003) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO Journal 22, 4082-4090

29 P.J. Kallio (1998) Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha EMBO Journal 17, 6573-6586

30 G.L. Wang and G.L. Semenza (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proceedings of the National Academy of Sciences of the United States of America 90, 4304-4308

31 K.S. Hewitson (2002) Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. Journal of Biological Chemistry 277, 26351-26355

32 D. Lando (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes and Development 16, 1466-1471

33 D. Lando (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295, 858-861

34 L.A. McNeill (2002) Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the beta-carbon of asparagine-803. The Biochemical Journal 367, 571-575

35 P.C. Mahon , K. Hirota and G.L. Semenza (2001) FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes and Development 15, 2675-2686

36 G.L. Semenza (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annual Review of Cell and Developmental Biology 15, 551-578

39 V.A. Carroll and M. Ashcroft (2006) Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Research 66, 6264-6270

40 V. Compernolle (2002) Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nature Medicine 8, 702-710

41 C.J. Hu (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Molecular and Cellular Biology 23, 9361-9374

42 M. Krieg (2000) Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 19, 5435-5443

43 R.R. Raval (2005) Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Molecular and Cellular Biology 25, 5675-5686

45 M.A. Maynard (2003) Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. Journal of Biological Chemistry 278, 11032-11040

46 Y. Makino (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414, 550-554

47 Y. Makino (2007) Transcriptional up-regulation of inhibitory PAS domain protein gene expression by hypoxia-inducible factor 1 (HIF-1): a negative feedback regulatory circuit in HIF-1-mediated signaling in hypoxic cells. Journal of Biological Chemistry 282, 14073-14082

48 J.J. Briere (2006) Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation. American Journal of Physiology – Cell Physiology 291, C1114-1120

49 P.J. Pollard (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Human Molecular Genetics 14, 2231-2239

50 E. Berra , G. Pages and J. Pouyssegur (2000) MAP kinases and hypoxia in the control of VEGF expression. Cancer and Metastasis Reviews 19, 139-145

51 R. Karni (2002) Activated pp60c-Src leads to elevated hypoxia-inducible factor (HIF)-1alpha expression under normoxia. Journal of Biological Chemistry 277, 42919-42925

52 B.L. Lee (2008) A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angiogenesis in human gastric cancer. Carcinogenesis 29, 44-51

54 J.I. Bardos and M. Ashcroft (2004) Hypoxia-inducible factor-1 and oncogenic signalling. Bioessays 26, 262-269

56 K. Miyake (2008) Expression of hypoxia-inducible factor-1alpha, histone deacetylase 1, and metastasis-associated protein 1 in pancreatic carcinoma: correlation with poor prognosis with possible regulation. Pancreas 36, e1-9

57 M.I. Koukourakis (2002) Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. International Journal of Radiation Oncology Biology Physics 53, 1192-1202

58 S.C. Winter (2006) The relation between hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer. Cancer 107, 757-766

60 R. Bos (2003) Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97, 1573-1581

61 G. Gruber (2004) Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter? Breast Cancer Research 6, R191-198

62 T. Klatte (2007) Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma. Clinical Cancer Research 13, 7388-7393

64 H.L. Ke (2008) Overexpression of hypoxia-inducible factor-1alpha predicts an unfavorable outcome in urothelial carcinoma of the upper urinary tract. International Journal of Urology 15, 200-205

65 K.L. Talks (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. American Journal of Pathology 157, 411-421

66 T. Fillies (2005) HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor. BMC Cancer 5, 84

67 Y. Sumiyoshi (2006) Overexpression of hypoxia-inducible factor 1alpha and p53 is a marker for an unfavorable prognosis in gastric cancer. Clinical Cancer Research 12, 5112-5117

68 P.H. Maxwell (2005) The HIF pathway in cancer. Seminars in Cell and Developmental Biology 16, 523-530

69 L. Bastien (2009) Targeted therapies in metastatic renal cancer in 2009. BJU International 103, 1334–42

70 E.J. Yeo , Y.S. Chun and J.W. Park (2004) New anticancer strategies targeting HIF-1. Biochemical Pharmacology 68, 1061-1069

71 J. Chen (2003) Dominant-negative hypoxia-inducible factor-1 alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. American Journal of Pathology 162, 1283-1291

72 G. Zinzalla and D.E. Thurston (2009) Targeting protein–protein interactions for therapeutic intervention: a challenge for the future. Future Medicinal Chemistry 1, 65-93

74 A.L. Kung (2004) Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 6, 33-43

75 S.H. Li (2008) A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1{alpha}. Molecular Cancer Therapeutics 7, 3729-3738

76 E.J. Yeo (2003) YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. Journal of the National Cancer Institute 95, 516-525

77 E.J. Park (2006) Targeting the PAS-A domain of HIF-1alpha for development of small molecule inhibitors of HIF-1. Cell Cycle 5, 1847-1853

79 H.J. Choi (2008) Rapid degradation of hypoxia-inducible factor-1alpha by KRH10 2053, a new activator of prolyl hydroxylase 2. British Journal of Pharmacology 154, 114-125

80 K. Nakayama (2004) Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell 117, 941-952

81 A. Moller (2009) Inhibition of Siah ubiquitin ligase function. Oncogene 28, 289-296

82 T. Soussi and G. Lozano (2005) p53 mutation heterogeneity in cancer. Biochemical and Biophysical Research Communications 331, 834-842

83 A.J. Levine (1997) p53 the cellular gatekeeper for growth and division. Cell 88, 323-331

84 K.H. Vousden and D.P. Lane (2007) p53 in health and disease. Nature Reviews Molecular Cell Biology 8, 275-283

85 N.C. Denko (2000) p53 checkpoint-defective cells are sensitive to X rays, but not hypoxia. Experimental Cell Research 258, 82-91

86 A.J. Giaccia and M.B. Kastan (1998) The complexity of p53 modulation: emerging patterns from divergent signals. Genes and Development 12, 2973-2983

87 T.G. Graeber (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88-91

89 M.V. Blagosklonny (1998) p53 inhibits hypoxia-inducible factor-stimulated transcription. Journal of Biological Chemistry 273, 11995-11998

91 J. Yang (2009) Small molecule activation of p53 blocks HIF-1{alpha} and VEGF expression in vivo and leads to tumor cell apoptosis in normoxia and hypoxia. Molecular and Cellular Biology 29, 2243-2253

92 N. Sanchez-Puig , D.B. Veprintsev and A.R. Fersht (2005) Binding of natively unfolded HIF-1alpha ODD domain to p53. Molecular Cell 17, 11-21

93 T. Schmid (2004) p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). The Biochemical Journal 380, 289-295

94 D. Chen (2003) Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function. Journal of Biological Chemistry 278, 13595-13598

95 A.L. Nieminen (2005) Mdm2 and HIF-1alpha interaction in tumor cells during hypoxia. Journal of Cellular Physiology 204, 364-369

96 V.J. Bykov and K.G. Wiman (2003) Novel cancer therapy by reactivation of the p53 apoptosis pathway. Annals of Medicine 35, 458-465

97 B.A. Foster (1999) Pharmacological rescue of mutant p53 conformation and function. Science 286, 2507-2510

98 N. Issaeva (2004) Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nature Medicine 10, 1321-1328

99 L.T. Vassilev (2004) Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 3, 419-421

100 N.M. Chau (2005) Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors. Cancer Research 65, 4918-4928

103 A. Rapisarda (2004) Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Research 64, 6845-6848

104 M.Y. Koh (2008) Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Molecular Cancer Therapeutics 7, 90-100

105 G.R. Macpherson and W.D. Figg (2004) Small molecule-mediated anti-cancer therapy via hypoxia-inducible factor-1 blockade. Cancer Biology and Therapy 3, 503-504

107 H. Manabe (2008) Inhibition of histone deacetylase down-regulates the expression of hypoxia-induced vascular endothelial growth factor by rheumatoid synovial fibroblasts. Inflammation Research 57, 4-10

108 Y. Mie Lee (2003) Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity. Biochemical and Biophysical Research Communications 300, 241-246

109 Y. Sasakawa (2003) Effects of FK228, a novel histone deacetylase inhibitor, on tumor growth and expression of p21 and c-myc genes in vivo. Cancer Letters 195, 161-168

110 Y. Sasakawa (2003) Antitumor efficacy of FK228, a novel histone deacetylase inhibitor, depends on the effect on expression of angiogenesis factors. Biochemical Pharmacology 66, 897-906

112 O. Alqawi , M. Moghaddas and G. Singh (2006) Effects of geldanamycin on HIF-1alpha mediated angiogenesis and invasion in prostate cancer cells. Prostate Cancer and Prostatic Diseases 9, 126-135

113 J.S. Isaacs (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. Journal of Biological Chemistry 277, 29936-29944

114 W.Y. Kim (2009) Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1alpha. Cancer Research 69, 1624-1632

116 Y.V. Liu (2007) RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Molecular Cell 25, 207-217

117 H. Zhang (2008) Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proceedings of the National Academy of Sciences of the United States of America 105, 19579-19586

118 J.D. Gordan (2007) HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11, 335-347

119 J.D. Gordan (2008) HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14, 435-446

120 H.H. Chen (2007) Hypoxia-inducible factor-1alpha correlates with MET and metastasis in node-negative breast cancer. Breast Cancer Research and Treatment 103, 167-175

121 S. Hara (2006) Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells. Oral Oncology 42, 593-598

122 M. Hayashi (2005) Up-regulation of c-met protooncogene product expression through hypoxia-inducible factor-1alpha is involved in trophoblast invasion under low-oxygen tension. Endocrinology 146, 4682-4689

123 J.H. Lim (2004) Ras-dependent induction of HIF-1alpha785 via the Raf/MEK/ERK pathway: a novel mechanism of Ras-mediated tumor promotion. Oncogene 23, 9427-9431

124 R.H. Giles (2006) Interplay between VHL/HIF1alpha and Wnt/beta-catenin pathways during colorectal tumorigenesis. Oncogene 25, 3065-3070

125 Y. Jiang (2007) Hypoxia induces transforming growth factor-beta1 gene expression in the pulmonary artery of rats via hypoxia-inducible factor-1alpha. Acta Biochimica et Biophysica Sinica (Shanghai) 39, 73-80

126 A. Kaidi , A.C. Williams and C. Paraskeva (2007) Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nature Cell Biology 9, 210-217

127 K.L. Covello , M.C. Simon and B. Keith (2005) Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Cancer Research 65, 2277-2286

128 C.J. Hu (2006) Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells. Molecular and Cellular Biology 26, 3514-3526

130 E.B. Rankin (2008) Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene 27, 5354-5358

131 P. Silva (2008) Prognostic significance of tumor hypoxia inducible factor-1alpha expression for outcome after radiotherapy in oropharyngeal cancer. International Journal of Radiation Oncology Biology Physics 72, 1551-1559

132 C. Tzao (2008) Expression of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF)-D as outcome predictors in resected esophageal squamous cell carcinoma. Disease Markers 25, 141-148

133 M. Uehara (2009) Hypoxia-inducible factor 1 alpha in oral squamous cell carcinoma and its relation to prognosis. Oral Oncology 45, 241-246

134 C. Trastour (2007) HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. International Journal of Cancer 120, 1451-1458

135 R.J. Motzer (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. New England Journal of Medicine 356, 115-124

136 R.J. Motzer (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 24, 16-24

137 M.J. Ratain (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 24, 2505-2512

138 M.F. O'Brien , P. Russo and R.J. Motzer (2008) Sunitinib therapy in renal cell carcinoma. BJU International 101, 1339-1342

139 S. Turcotte (2008) A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14, 90-102

140 A. Bommi-Reddy (2008) Kinase requirements in human cells: III. Altered kinase requirements in VHL−/− cancer cells detected in a pilot synthetic lethal screen. Proceedings of the National Academy of Sciences of the United States of America 105, 16484-16489

141 C.M. Doll (2003) Estimating hypoxic status in human tumors: a simulation using Eppendorf oxygen probe data in cervical cancer patients. International Journal of Radiation Oncology Biology Physics 55, 1239-1246

142 B. Movsas (2001) Hypoxia in human prostate carcinoma: an Eppendorf PO2 study. American Journal of Clinical Oncology 24, 458-461

146 A. Brahme (2003) Biologically optimized 3-dimensional in vivo predictive assay-based radiation therapy using positron emission tomography-computerized tomography imaging. Acta Oncologica 42, 123-136

147 A.R. Padhani (2007) Imaging oxygenation of human tumours. European Radiology 17, 861-872

148 J.G. Rajendran and K.A. Krohn (2005) Imaging hypoxia and angiogenesis in tumors. Radiologic Clinics of North America 43, 169-187

149 B. Gagel (2006) [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography in response evaluation after chemo-/radiotherapy of non-small-cell lung cancer: a feasibility study. BMC Cancer 6, 51

150 J.G. Rajendran (2006) Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clinical Cancer Research 12, 5435-5441

151 D. Thorwarth (2006) Combined uptake of [18F]FDG and [18F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients. Radiotherapy and Oncology 80, 151-156

152 E.G. Troost (2008) Correlation of [18F]FMISO autoradiography and pimonodazole immunohistochemistry in human head and neck carcinoma xenografts. European Journal of Nuclear Medicine and Molecular Imaging 35, 1803-1811

153 E.M. Hendriksen (2009) Angiogenesis, hypoxia and VEGF expression during tumour growth in a human xenograft tumour model. Microvascular Research 77, 96-103

154 D. Kong (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Research 65, 9047-9055

155 D.T. Jones and A.L. Harris (2006) Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding. Molecular Cancer Therapeutics 5, 2193-2202

156 X. Lin (2008) A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation. Proceedings of the National Academy of Sciences of the United States of America 105, 174-179

157 K. Lee (2009) Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proceedings of the National Academy of Sciences of the United States of America 106, 2353-2358

158 L.M. Greenberger (2008) A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. Molecular Cancer Therapeutics 7, 3598-3608

159 Z.G. Dikmen (2008) In vivo and in vitro effects of a HIF-1alpha inhibitor, RX-0047. Journal of Cellular Biochemistry 104, 985-994

161 P. Buchler (2004) Antiangiogenic activity of genistein in pancreatic carcinoma cells is mediated by the inhibition of hypoxia-inducible factor-1 and the down-regulation of VEGF gene expression. Cancer 100, 201-210

162 K.B. Sandau , H.G. Faus and B. Brune (2000) Induction of hypoxia-inducible-factor 1 by nitric oxide is mediated via the PI 3K pathway. Biochemical and Biophysical Research Communications 278, 263-267

163 K.B. Sandau (2001) Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide. Journal of Biological Chemistry 276, 39805-39811

164 B. Wang (2005) Genistein inhibited hypoxia-inducible factor-1alpha expression induced by hypoxia and cobalt chloride in human retinal pigment epithelium cells. Methods and Findings in Experimental and Clinical Pharmacology 27, 179-184

165 M. Calvani (2008) Differential involvement of vascular endothelial growth factor in the survival of hypoxic colon cancer cells. Cancer Research 68, 285-291

166 Y. Lu (2007) Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1alpha. Molecular Cancer 6, 63

167 R.B. Luwor (2005) The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene 24, 4433-4441

168 N. Pore (2006) EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Research 66, 3197-3204

170 K.M. Sutton (2007) Selective inhibition of MEK1/2 reveals a differential requirement for ERK1/2 signalling in the regulation of HIF-1 in response to hypoxia and IGF-1. Oncogene 26, 3920-3929

171 S.M. Kumar (2007) Mutant V600E BRAF increases hypoxia inducible factor-1alpha expression in melanoma. Cancer Research 67, 3177-3184

172 N. Pore (2006) Nelfinavir down-regulates hypoxia-inducible factor 1alpha and VEGF expression and increases tumor oxygenation: implications for radiotherapy. Cancer Research 66, 9252-9259

173 N. Pore (2006) HIV protease inhibitors decrease VEGF/HIF-1alpha expression and angiogenesis in glioblastoma cells. Neoplasia 8, 889-895

174 P. Garcia-Maceira and J. Mateo (2009) Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy. Oncogene 28, 313-324

175 G.D. Stewart (2009) NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway. International Journal of Cancer 124, 223-232

176 E. Pencreach (2009) Marked activity of irinotecan and rapamycin combination toward colon cancer cells in vivo and in vitro is mediated through cooperative modulation of the mammalian target of rapamycin/hypoxia-inducible factor-1alpha axis. Clinical Cancer Research 15, 1297-1307

178 X. Wan (2006) CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia 8, 394-401

179 D. Cejka (2008) Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biology and Therapy 7, 1377-1385

180 S. Mabuchi (2007) RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clinical Cancer Research 13, 4261-4270

181 J. Fang (2007) Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. Carcinogenesis 28, 858-864

183 S. Mirzoeva (2008) Inhibition of HIF-1 alpha and VEGF expression by the chemopreventive bioflavonoid apigenin is accompanied by Akt inhibition in human prostate carcinoma PC3-M cells. Molecular Carcinogenesis 47, 686-700

184 M. Osada , S. Imaoka and Y. Funae (2004) Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1alpha protein. FEBS Letters 575, 59-63

186 C.K. Lau (2006) Suppression of hypoxia inducible factor-1alpha (HIF-1alpha) by YC-1 is dependent on murine double minute 2 (Mdm2). Biochemical and Biophysical Research Communications 348, 1443-1448

187 H.L. Sun (2007) YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia. Oncogene 26, 3941-3951

188 Q. Zhao (2007) Effects of YC-1 on hypoxia-inducible factor 1-driven transcription activity, cell proliferative vitality, and apoptosis in hypoxic human pancreatic cancer cells. Pancreas 34, 242-247

189 S.P. Huang (2005) Cyclooxygenase-2 increases hypoxia-inducible factor-1 and vascular endothelial growth factor to promote angiogenesis in gastric carcinoma. Journal of Biomedical Science 12, 229-241

191 H. Zhong , M. Willard and J. Simons (2004) NS398 reduces hypoxia-inducible factor (HIF)-1alpha and HIF-1 activity: multiple-level effects involving cyclooxygenase-2 dependent and independent mechanisms. International Journal of Cancer 112, 585-595

193 D.M. Fath (2006) Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha. Journal of Biological Chemistry 281, 13612-13619

194 D.Z. Qian (2004) The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Research 64, 6626-6634

195 S.L. Thomas (2008) EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1. Cell Cycle 7, 2409-2417

196 N.J. Mabjeesh (2003) 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 3, 363-375

197 S.L. Mooberry (2003) Mechanism of action of 2-methoxyestradiol: new developments. Drug Resistance Updates 6, 355-361

198 J.L. Ricker (2004) 2-methoxyestradiol inhibits hypoxia-inducible factor 1alpha tumor growth, and angiogenesis and augments paclitaxel efficacy in head and neck squamous cell carcinoma. Clinical Cancer Research 10, 8665-8673

199 T.M. LaVallee (2008) Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198. Molecular Cancer Therapeutics 7, 1472-1482

200 C. Moser (2008) ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma(HCC) cells, and inhibits growth and vascularization in vivo. BMC Cancer 8, 206

201 H.S. Kim (2008) Paclitaxel induces vascular endothelial growth factor expression through reactive oxygen species production. Pharmacology 81, 317-324

202 B. Vlaminck (2007) Dual effect of echinomycin on hypoxia-inducible factor-1 activity under normoxic and hypoxic conditions. FEBS Journal 274, 5533-5542

203 B.Z. Olenyuk (2004) Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proceedings of the National Academy of Sciences of the United States of America 101, 16768-16773

204 M.C. Duyndam (2007) Cisplatin and doxorubicin repress Vascular Endothelial Growth Factor expression and differentially down-regulate Hypoxia-inducible Factor I activity in human ovarian cancer cells. Biochemical Pharmacology 74, 191-201

205 G.A. LaRusch (2007) Nutlin3 blocks vascular endothelial growth factor induction by preventing the interaction between hypoxia inducible factor 1alpha and Hdm2. Cancer Research 67, 450-454

206 B.F. Jordan (2005) Metabolite changes in HT-29 xenograft tumors following HIF-1alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo. NMR in Biomedicine 18, 430-439

207 B.F. Jordan (2005) Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1alpha using PX-478. Neoplasia 7, 475-485

208 S.T. Palayoor (2008) PX-478, an inhibitor of hypoxia-inducible factor-1alpha, enhances radiosensitivity of prostate carcinoma cells. International Journal of Cancer 123, 2430-2437

209 C. Werno , J. Zhou and B. Brune (2008) A23187, ionomycin and thapsigargin upregulate mRNA of HIF-1alpha via endoplasmic reticulum stress rather than a rise in intracellular calcium. Journal of Cellular Physiology 215, 708-714

210 K. Zhu (2009) Control of HIF-1alpha expression by eIF2 alpha phosphorylation-mediated translational repression. Cancer Research 69, 1836-1843

211 A. Rapisarda and G. Melillo (2007) UVC inhibits HIF-1alpha protein translation by a DNA damage- and topoisomerase I-independent pathway. Oncogene 26, 6875-6884

212 M. Puppo (2008) Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1alpha and -2alpha. Molecular Cancer Therapeutics 7, 1974-1984

213 M. Creighton-Gutteridge (2007) Cell type-specific, topoisomerase II-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation by NSC 644221. Clinical Cancer Research 13, 1010-1018

214 H. Kamiyama (2005) Anti-angiogenic effects of SN38 (active metabolite of irinotecan): inhibition of hypoxia-inducible factor 1 alpha (HIF-1alpha)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells. Journal of Cancer Research and Clinical Oncology 131, 205-213

215 M. Maeda (2006) Inhibition of angiogenesis and HIF-1alpha activity by antimycin A1. Biological and Pharmaceutical Bulletin 29, 1344-1348

216 T. Hagen (2003) Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1alpha. Science 302, 1975-1978

217 C. Xia (2007) Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Research 67, 10823-10830

220 H. Yasui (2008) Inhibition of HIF-1alpha by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo. British Journal of Cancer 99, 1442-1452

221 L. Zeng (2008) TS-1 enhances the effect of radiotherapy by suppressing radiation-induced hypoxia-inducible factor-1 activation and inducing endothelial cell apoptosis. Cancer Science 99, 2327-2335

222 H. Wu (2008) Resveratrol inhibits hypoxia-induced metastasis potential enhancement by restricting hypoxia-induced factor-1 alpha expression in colon carcinoma cells. Biomedicine and Pharmacotherapy 62, 613-621

223 E.W. Newcomb (2005) Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1alpha expression in human glioma cells by a proteasome-independent pathway: implications for in vivo therapy. Neuro-Oncology 7, 225-235

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Expert Reviews in Molecular Medicine
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