Small-molecule inhibitors of the HIF pathway and synthetic lethal interactions

Expert Opinion on Therapeutic Targets

Volumn 16, Issue 5, 2012, Pages 463-480

  Jones, Dylan T ^a   Harris, Adrian L ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Angiogenesis; HIF; Hypoxia

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; 4 [BIS(2 CHLOROETHYL)OXIDOAMINO]PHENYLALANINE; AJM 290; ALVESPIMYCIN; ARC 155858; CAMPTOTHECIN; DACINOSTAT; DJ 12; ENMD 1198; EVEROLIMUS; EZN 2968; GANETESPIB; GELDANAMYCIN; HEAT SHOCK PROTEIN 90 INHIBITOR; HISTONE DEACETYLASE INHIBITOR; HYPOXIA INDUCIBLE FACTOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 2ALPHA; HYPOXIA INDUCIBLE FACTOR INHIBITOR; KRH 102053; KRH 102140; LIFICIGUAT; MK 2206; NATURAL PRODUCT; NSC 50352; NSC 644221; NSC 652287; NVPLAQ 824; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PMX 464; PROTEIN INHIBITOR; PX 12; RAPAMYCIN; ROMIDEPSIN; TANESPIMYCIN; TEMSIROLIMUS; THS 044; TOPOTECAN; TRICHOSTATIN A; UNCLASSIFIED DRUG; UNINDEXED DRUG; VORINOSTAT; WORTMANNIN;

ANTINEOPLASTIC ACTIVITY; CANCER CELL CULTURE; CELL ASSAY; CELL MIGRATION; CELL PROLIFERATION; CHROMATIN IMMUNOPRECIPITATION; CYTOTOXICITY; DIMERIZATION; DRUG POTENCY; DRUG SYNTHESIS; DRUG TARGETING; FOOD AND DRUG ADMINISTRATION; GENE MUTATION; GENE TARGETING; GROWTH INHIBITION; HUMAN; HYPOXIA; IN VITRO STUDY; MOLECULARLY TARGETED THERAPY; MOLECULE; NONHUMAN; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; PROTEIN SYNTHESIS; REVIEW; RNA TRANSLATION; SIGNAL TRANSDUCTION;

ANIMALS; ANOXIA; ANTINEOPLASTIC AGENTS; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; DRUG DESIGN; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; MOLECULAR TARGETED THERAPY; NEOPLASMS; UP-REGULATION;

EID: 84860226814     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2012.674516     Document Type: Review

References (139)

1. Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 2006;59:15-26
2. Heikkila M, Pasanen A, Kivirikko KI, Myllyharju J. Roles of the human hypoxia-inducible factor (HIF)-3alpha variants in the hypoxia response. Cell Mol Life Sci 2011;68:3885-3901
3. Koivunen P, Tiainen P, Hyvarinen J, et al. An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. J Biol Chem 2007;282:30544-52
4. Berra E, Benizri E, Ginouves A, et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J 2003;22:4082-4090
5. Bishop T, Gallagher D, Pascual A, et al. Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice. Mol Cell Biol 2008;28:3386-3400
6. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004;5:343-354
7. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: Implications for tumor angiogenesis and therapeutics. Cancer Res 2000;60:1541-1545
8. Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 2008;8:851-864
9. van Uden P, Kenneth NS, Rocha S. Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J 2008;412:477-484
10. Welsh SJ, Williams RR, Birmingham A, et al. The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation. Mol Cancer Ther 2003;2:235-243
11. Neckers L. Heat shock protein 90: The cancer chaperone. J Biosci 2007;32:517-530
12. Miyake K, Yoshizumi T, Imura S, et al. 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 2008;36:e1-9
13. Flugel D, Gorlach A, Kietzmann T. Gsk-3beta regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1alpha. Blood 2012;119:1292-1301
14. Ravi R, Mookerjee B, Bhujwalla ZM, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 2000;14:34-44
15. Mylonis I, Chachami G, Samiotaki M, et al. Identification of MAPK phosphorylation sites and their role in the localisation and activity of hypoxia-inducible factor-1alpha. J Biol Chem 2006;281:33095-106
16. Suzuki H, Tomida A, Tsuruo T. Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 2001;20:5779-5788
17. Ndubuizu OI, Tsipis CP, Li A, LaManna JC. Hypoxia-inducible factor-1 (HIF-1)-independent microvascular angiogenesis in the aged rat brain. Brain Res 2010;1366:101-109
18. Mole DR, Blancher C, Copley RR, et al. Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem 2009;284:16767-75
19. Schodel J, Oikonomopoulos S, Ragoussis J, et al. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood 2011;117:e207-17
20. Gillespie DL, Whang K, Ragel BT, et al. Silencing of hypoxia inducible factor-1alpha by RNA interference attenuates human glioma cell growth in vivo. Clin Cancer Res 2007;13:2441-2448
21. Kamlah F, Eul BG, Li S, et al. Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a lewis lung carcinoma cancer model. Cancer Gene Ther 2009;16:195-205
22. Raval RR, Lau KW, Tran MG, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-Associated renal cell carcinoma. Mol Cell Biol 2005;25:5675-5686
23. Loboda A, Jozkowicz A, Dulak J. HIF-1 and HIF-2 transcription factors - similar but not identical. Mol Cells 2010;29:435-442
24. Hers I, Vincent EE, Tavare JM. Akt signalling in health and disease. Cell Signal 2011;23:1515-1527
25. Koh MY, Spivak-Kroizman TR, Powis G. Inhibiting the hypoxia response for cancer therapy: The new kid on the block. Clin Cancer Res 2009;15:5945-5946
26. Cejka D, Preusser M, Woehrer A, et al. Everolimus (RAD001) and anti-Angiogenic cyclophosphamide show long-Term control of gastric cancer growth in vivo. Cancer Biol Ther 2008;7:1377-1385
27. Wysocki PJ. mTOR in renal cell cancer: Modulator of tumor biology and therapeutic target. Expert Rev Mol Diagn 2009;9:231-241
28. Holmgren A, Lu J. Thioredoxin and thioredoxin reductase: Current research with special reference to human disease. Biochem Biophys Res Commun 2010;396:120-124
29. Mukherjee A, Huber K, Evans H, et al. A cellular and molecular investigation of the action of PMX464, a putative thioredoxin inhibitor, in normal and colorectal cancer cell lines. Br J Pharmacol 2007;151:1167-1175
30. Jones DT, Pugh CW, Wigfield S, et al. Novel thioredoxin inhibitors paradoxically increase hypoxia-inducible factor-Alpha expression but decrease functional transcriptional activity, DNA binding, and degradation. Clin Cancer Res 2006;12:5384-5394
31. Ramanathan RK, Abbruzzese J, Dragovich T, et al. A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination. Cancer Chemother Pharmacol 2011;67:503-509
32. Ramanathan RK, Stephenson JJ, Weiss GJ, et al. A phase I trial of PX-12, a small-molecule inhibitor of thioredoxin-1, administered as a 72-h infusion every 21 days in patients with advanced cancers refractory to standard therapy. Invest New Drugs 2011;published online 24 August 2011; doi 10.1007/s10637-011- 9739-9
33. Rapisarda A, Shoemaker RH, Melillo G. Targeting topoisomerase I to inhibit hypoxia inducible factor 1. Cell Cycle 2004;3:172-175
34. Choi YJ, Rho JK, Lee SJ, et al. HIF-1alpha modulation by topoisomerase inhibitors in non-small cell lung cancer cell lines. J Cancer Res Clin Oncol 2009;135:1047-1053
35. Creighton-Gutteridge M, Cardellina JH II, Stephen AG, et al. Cell type-specific, topoisomerase II-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation by NSC 644221. Clin Cancer Res 2007;13:1010-1018
36. Johnstone RW. Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer. Nat Rev Drug Discov 2002;1:287-299
37. Yang QC, Zeng BF, Shi ZM, et al. Inhibition of hypoxia-induced angiogenesis by trichostatin A via suppression of HIF-1a activity in human osteosarcoma. J Exp Clin Cancer Res 2006;25:593-599
38. Naldini A, Filippi I, Cini E, et al. Downregulation of hypoxia-related responses by novel antitumor histone deacetylase inhibitors in MDAMB231 breast cancer cells. Anticancer Agents Med Chem 2011;published online 25 October 2011; doi: BSP/ACAMC/E-Pub/00056
39. Mie Lee Y, Kim SH, Kim HS, et al. Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity. Biochem Biophys Res Commun 2003;300:241-246
40. De Bono JS, Kristeleit R, Tolcher A, et al. Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors. Clin Cancer Res 2008;14:6663-6673
41. Muhlethaler-Mottet A, Meier R, Flahaut M, et al. Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-Tumour activity in neuroblastoma cells. Mol Cancer 2008;7:55
42. VanderMolen KM, McCulloch W, Pearce CJ, Oberlies NH. Romidepsin (istodax, NSC 630176, FR901228, FK228, depsipeptide): A natural product recently approved for cutaneous T-cell lymphoma. J Antibiot (Tokyo) 2011;64:525-531
43. Piekarz RL, Frye R, Prince HM, et al. Phase II trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 2011;117:5827-5834
44. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004;4:253-265
45. Mabjeesh NJ, Escuin D, LaVallee TM, et al. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 2003;3:363-375
46. Tevaarwerk AJ, Holen KD, Alberti DB, et al. Phase I trial of 2-methoxyestradiol NanoCrystal dispersion in advanced solid malignancies. Clin Cancer Res 2009;15:1460-1465
47. Bruce JY, Eickhoff J, Pili R, et al. A phase II study of 2-methoxyestradiol nanocrystal colloidal dispersion alone and in combination with sunitinib malate in patients with metastatic renal cell carcinoma progressing on sunitinib malate. Invest New Drugs 2012;30:794-802
48. LaVallee TM, Burke PA, Swartz GM, et al. Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198. Mol Cancer Ther 2008;7:1472-1482
49. Zhou Q, Gustafson D, Nallapareddy S, et al. A phase I dose-escalation, safety and pharmacokinetic study of the 2-methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer. Invest New Drugs 2011;29:340-346
50. Usmani SZ, Bona R, Li Z. 17 AAG for HSP90 inhibition in cancer-from bench to bedside. Curr Mol Med 2009;9:654-664
51. Niu G, Li Z, Cao Q, et al. Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with 64Cu-DOTA-Trastuzumab. Eur J Nucl Med Mol Imaging 2009;36:1510-1519
52. Modi S, Stopeck A, Linden H, et al. HSP90 inhibition is effective in breast cancer: A Phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 2011;17:5132-5139
53. Kummar S, Gutierrez ME, Gardner ER, et al. Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur J Cancer 2010;46:340-347
54. Wang Y, Trepel JB, Neckers LM, Giaccone G. Sta-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs 2010;11:1466-1476
55. Nepal M, Gong YD, Park YR, Soh Y. An activator of PHD2, KRH102140, decreases angiogenesis via inhibition of HIF-1alpha. Cell Biochem Funct 2011;29:126-134
56. Choi HJ, Song BJ, Gong YD, et al. Rapid degradation of hypoxia-inducible factor-1alpha by KRH102053, a new activator of prolyl hydroxylase 2. Br J Pharmacol 2008;154:114-125
57. Schmid T, Zhou J, Kohl R, Brune B. P300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (hif-1). Biochem J 2004;380:289-295
58. Issaeva N, Bozko P, Enge M, et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 2004;10:1321-1328
59. Yang J, Ahmed A, Poon E, et al. Small-molecule activation of p53 blocks hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in vivo and leads to tumor cell apoptosis in normoxia and hypoxia. Mol Cell Biol 2009;29:2243-2253
60. Greenberger LM, Horak ID, Filpula D, et al. A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 2008;7:3598-3608
61. Lewis N, Cohen RB, Nishida Y, et al. Phase I, pharmacokinetic (PK), dose-escalation study of EZN-2968, a novel hypoxia-inducible factor-1alpha (HIF-1alpha) rna antagonist, administered weekly in patients (pts) with solid tumors. Available from: Http://enzon.com/files/HIF1a-2.pdf [Last accessed 19 March 2012]
62. Jiang M, Wang B, Wang C, et al. Inhibition of hypoxia-inducible factor-1alpha and endothelial progenitor cell differentiation by adenoviral transfer of small interfering RNA in vitro. J Vasc Res 2006;43:511-521
63. Jensen RL, Ragel BT, Whang K, Gillespie D. Inhibition of hypoxia inducible factor-1alpha (HIF-1alpha) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas. J Neurooncol 2006;78:233-247
64. Kong D, Park EJ, Stephen AG, et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 2005;65:9047-9055
65. Marshall ME, Wolf MK, Crawford ED, et al. Phase II trial of echinomycin for the treatment of advanced renal cell carcinoma. A Southwest Oncology Group study. Invest New Drugs 1993;11:207-209
66. Duyndam MC, van Berkel MP, Dorsman JC, et al. Cisplatin and doxorubicin repress vascular endothelial growth factor expression and differentially down-regulate hypoxia-inducible factor I activity in human ovarian cancer cells. Biochem Pharmacol 2007;74:191-201
67. Lee K, Qian DZ, Rey S, et al. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc. Natl. Acad. Sci. USA 2009;106:2353-2358
68. Nickols NG, Jacobs CS, Farkas ME, Dervan PB. Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface. ACS Chem Biol 2007;2:561-571
69. Jones DT, Harris AL. Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding. Mol Cancer Ther 2006;5:2193-2202
70. Kung AL, Zabludoff SD, France DS, et al. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 2004;6:33-43
71. Staab A, Loeffler J, Said HM, et al. Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells. BMC Cancer 2007;7:213
72. Lee K, Zhang H, Qian DZ, et al. Acriflavine inhibits HIF-1 dimerisation, tumor growth, and vascularisation. Proc. Natl. Acad. Sci. USA 2009;106:17910-15
73. Park EJ, Kong D, Fisher R, et al. Targeting the PAS-A domain of HIF-1alpha for development of small molecule inhibitors of HIF-1. Cell Cycle 2006;5:1847-1853
74. Scheuermann TH, Tomchick DR, Machius M, et al. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc. Natl. Acad. Sci. USA 2009;106:450-455
75. Li SH, Shin DH, Chun YS, et al. A novel mode of action of YC-1 in HIF inhibition: Stimulation of FIH-dependent p300 dissociation from HIF-1alpha. Mol Cancer Ther 2008;7:3729-3738
76. Lee K, Kim HM. A novel approach to cancer therapy using PX-478 as a HIF-1alpha inhibitor. Arch Pharm Res 2011;34:1583-1585
77. Semenza GL. HIF-1: Mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 2000;88:1474-1480
78. Koh MY, Spivak-Kroizman T, Venturini S, et al. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol Cancer Ther 2008;7:90-100
79. Ferrara N. The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS, 2005, Part 3, 209-31
80. Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol 2004;26:211-244
81. Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: Bevacizumab (avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 2009;14:1131-1138
82. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol 2007;25:1539-1544
83. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-2550
84. Summers J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: Bevacizumab plus interferon for advanced renal cell carcinoma. Oncologist 2010;15:104-111
85. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666-2676
86. Allison M. Avastin's commercial march suffers setback. Nat Biotechnol 2010;28:879-880
87. Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15:220-231
88. Ebos JM, Lee CR, Cruz-Munoz W, et al. Accelerated metastasis after short-Term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009;15:232-239
89. Kurtoglu M, Maher JC, Lampidis TJ. Differential toxic mechanisms of 2-deoxy-d-glucose versus 2-fluorodeoxyd-glucose in hypoxic and normoxic tumor cells. Antioxid Redox Signal 2007;9:1383-1390
90. Floridi A, Paggi MG, Marcante ML, et al. Lonidamine, a selective inhibitor of aerobic glycolysis of murine tumor cells. J Natl Canc Inst 1981;66:497-499
91. Oudard S, Carpentier A, Banu E, et al. Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme. J Neurooncol 2003;63:81-86
92. Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 2005;202:654-662
93. Subbarayan PR, Wang PG, Lampidis TJ, et al. Differential expression of Glut 1 mRNA and protein levels correlates with increased sensitivity to the glyco-conjugated nitric oxide donor (2-glu-SNAP) in different tumor cell types. J Chemother 2008;20:106-111
94. Wood TE, Dalili S, Simpson CD, et al. A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death. Mol Cancer Ther 2008;7:3546-3555
95. Shimizu T, Okamoto I, Tamura K, et al. Phase I clinical and pharmacokinetic study of the glucose-conjugated cytotoxic agent D-19575 (glufosfamide) in patients with solid tumors. Cancer Chemother Pharmacol 2010;65:243-250
96. Semenza GL. Tumor metabolism: Cancer cells give and take lactate. J Clin Invest 2008;118:3835-3837
97. Busk M, Walenta S, Mueller-Klieser W, et al. Inhibition of tumor lactate oxidation: Consequences for the tumor microenvironment. Radiother Oncol 2011;99:404-411
98. Le Floch R, Chiche J, Marchiq I, et al. CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc. Natl. Acad. Sci. USA 2011;108:16663-8
99. Lou Y, McDonald PC, Oloumi A, et al. Targeting tumor hypoxia: Suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 2011;71:3364-3376
100. Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 2006;281:9030-9037
101. Shimoda LA, Fallon M, Pisarcik S, et al. HIF-1 regulates hypoxic induction of nhe1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 2006;291:L941-9
102. Chiche J, Ilc K, Laferriere J, et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 2009;69:358-368
103. Supuran CT. Carbonic anhydrases as drug targets - An overview. Curr Top Med Chem 2007;7:825-833
104. Pacchiano F, Carta F, McDonald PC, et al. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem 2011;54:1896-1902
105. Haddad RI, Weinstein LJ, Wieczorek TJ, et al. A Phase II clinical and pharmacodynamic study of E7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: Modulation of retinoblastoma protein phosphorylation by a novel chloroindolyl sulfonamide cell cycle inhibitor. Clin Cancer Res 2004;10:4680-4687
106. Nagle DG, Zhou YD. Natural product-derived small molecule activators of hypoxia-inducible factor-1 (HIF-1). Curr Pharm Des 2006;12:2673-2688
107. Hackenbeck T, Knaup KX, Schietke R, et al. HIF-1 or HIF-2 induction is sufficient to achieve cell cycle arrest in NIH3T3 mouse fibroblasts independent from hypoxia. Cell Cycle 2009;8:1386-1395
108. Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat Rev Cancer 2008;8:967-975
109. Roberts AM, Watson IR, Evans AJ, et al. Suppression of hypoxia-inducible factor 2alpha restores p53 activity via Hdm2 and reverses chemoresistance of renal carcinoma cells. Cancer Res 2009;69:9056-9064
110. Shen C, Beroukhim R, Schumacher SE, et al. Genetic and functional studies implicate HIF1alpha as a 14q kidney cancer suppressor gene. Cancer Discov 2011;1:222-235
111. Mazumdar J, Hickey MM, Pant DK, et al. HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc. Natl. Acad. Sci. USA 2010;107:14182-7
112. Acker T, Diez-Juan A, Aragones J, et al. Genetic evidence for a tumor suppressor role of HIF-2alpha. Cancer Cell 2005;8:131-141
113. Seddon BM, Honess DJ, Vojnovic B, et al. Measurement of tumor oxygenation: In vivo comparison of a luminescence fiber-optic sensor and a polarographic electrode in the p22 tumor. Radiat Res 2001;155:837-846
114. Wen B, Urano M, Humm JL, et al. Comparison of helzel and oxylite systems in the measurements of tumor partial oxygen pressure (pO2). Radiat Res 2008;169:67-75
115. Kaanders JH, Wijffels KI, Marres HA, et al. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res 2002;62:7066-7074
116. Padhani AR, Krohn KA, Lewis JS, Alber M. Imaging oxygenation of human tumours. Eur Radiol 2007;17:861-872
117. Padhani AR. Where are we with imaging oxygenation in human tumours? Cancer Imaging 2005;5:128-130
118. Troost EG, Laverman P, Philippens ME, et al. Correlation of [18F]FMISO autoradiography and pimonidazole immunohistochemistry in human head and neck carcinoma xenografts. Eur J Nucl Med Mol Imaging 2008;35:1803-1811
119. Jordan BF, Runquist M, Raghunand N, et al. 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 2005;7:475-485
120. Egeland TA, Gulliksrud K, Gaustad JV, et al. Dynamic contrast-enhanced- mri of tumor hypoxia. Magn Reson Med 2012;67:519-530
121. Lungu GF, Li ML, Xie X, et al. In vivo imaging and characterization of hypoxia-induced neovascularisation and tumor invasion. Int J Oncol 2007;30:45-54
122. Gagel B, Reinartz P, Demirel C, et al. [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 2006;6:51
123. Yang JJ, Wang SX, Zhong WZ, et al. Is 18F-fluorodeoxyglucose positron emission tomography-based metabolic response superior to response evaluation criteria in solid tumors-based response after two cycles of platinum-based chemotherapy in predicting clinical outcome of untreated patients with advanced non-small cell lung cancer? Nucl Med Commun 2011;32:1113-1120
124. Choi W, Lee SW, Park SH, et al. Planning study for available dose of hypoxic tumor volume using fluorine-18-labeled fluoromisonidazole positron emission tomography for treatment of the head and neck cancer. Radiother Oncol 2010;97:176-182
125. Rischin D, Hicks RJ, Fisher R, et al. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: A substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol 2006;24:2098-2104
126. Toustrup K, Sorensen BS, Lassen P, et al. Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol 2012;102:122-129
127. Schwartz DL, Powis G, Thitai-Kumar A, et al. The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects. Mol Cancer Ther 2009;8:947-958
128. Moon SY, Chang HW, Roh JL, et al. Using YC-1 to overcome the radioresistance of hypoxic cancer cells. Oral Oncol 2009;45:915-919
129. Palayoor ST, Mitchell JB, Cerna D, et al. PX-478, an inhibitor of hypoxia-inducible factor-1alpha, enhances radiosensitivity of prostate carcinoma cells. Int J Cancer 2008;123:2430-2437
130. Verheul HM, Salumbides B, Van Erp K, et al. Combination strategy targeting the hypoxia inducible factor-1alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 2008;14:3589-3597
131. Pencreach E, Guerin E, Nicolet C, et al. 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. Clin Cancer Res 2009;15:1297-1307
132. Reddy KR, Guan Y, Qin G, et al. Combined treatment targeting HIF-1alpha and Stat3 is a potent strategy for prostate cancer therapy. Prostate 2011;71:1796-1809
133. Barliya T, Mandel M, Livnat T, et al. Degradation of HIF-1alpha under hypoxia combined with induction of Hsp90 polyubiquitination in cancer cells by hypericin: A unique cancer therapy. PLoS One 2011;6:e22849
134. Rapisarda A, Hollingshead M, Uranchimeg B, et al. Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther 2009;8:1867-1877
135. De Bock K, Mazzone M, Carmeliet P. Antiangiogenic therapy, hypoxia, and metastasis: Risky liaisons, or not? Nat Rev Clin Oncol 2011;8:393-404
136. Rose PG, Smrekar M, Haba P, et al. A phase I/II trial of weekly topotecan and carboplatin in potentially platinum-sensitive relapsed ovarian and peritoneal carcinoma. Gynecol Oncol 2005;99:714-719
137. Altomare I, Bendell JC, Bullock KE, et al. A Phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer. Oncologist 2011;16:1131-1137
138. Bullock KE, Petros WP, Younis I, et al. A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE). Cancer Chemother Pharmacol 2011;67:465-474
139. Moroney JW, Schlumbrecht MP, Helgason T, et al. A Phase I trial of liposomal doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies. Clin Cancer Res 2011;17:6840-6846