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Targeting hypoxia cell signaling for cancer therapy

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Abstract

Hypoxia, a decrease in oxygen levels, is a hallmark of solid tumors. Hypoxic cells are more resistant to killing by ionizing radiation and chemotherapy, are more invasive and metastatic, resistant to apoptosis, and genetically unstable. Over the last two decades, the discovery of Hypoxia Inducible Factors, a family of transcription factors crucially involved in the response of mammalian cells to oxygen deprivation, has led to the identification of a molecular target associated with hypoxia suitable for the development of cancer therapeutics. These features of solid tumors may offer a unique opportunity for selective therapeutic approaches. A number of strategies targeting hypoxia and/or Hypoxia Inducible Factors (HIF) have been developed over the last several years and will be described. The exponentially growing interest in therapeutic strategies targeting hypoxia/HIF will undoubtedly generate more active compounds for preclinical and clinical development. A rational development plan aimed to validate target inhibition in preclinical models and early clinical trials is essential for a rapid translation of these agents to the treatment of human cancers.

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References

  1. Harris, A. L. (2002). Hypoxia—A key regulatory factor in tumour growth. Nature Reviews. Cancer, 2, 38–47.

    PubMed  CAS  Google Scholar 

  2. Brown, J. M, & Wilson, W. R. (2004). Exploiting tumour hypoxia in cancer treatment. Nature Reviews. Cancer, 4, 437–447.

    PubMed  CAS  Google Scholar 

  3. Melillo, G. (2006). Inhibiting hypoxia-inducible factor 1 for cancer therapy. Molecular Cancer Research, 4, 601–605.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  5. Giaccia, A., Siim, B. G., & Johnson, R. S. (2003). HIF-1 as a target for drug development. Nature Reviews. Drug Discovery, 2, 803–811.

    CAS  Google Scholar 

  6. Maxwell, P. H. (2005). The HIF pathway in cancer. Seminars in Cell & Developmental Biology, 16, 523–530.

    CAS  Google Scholar 

  7. Melillo, G. (2004). HIF-1: A target for cancer, ischemia and inflammation—Too good to be true? Cell Cycle, 3, 154–155.

    PubMed  CAS  Google Scholar 

  8. Kaufman, B., Scharf, O., Arbeit, J., Ashcroft, M., Brown, J. M., Bruick, R. K., et al. (2004). Proceedings of the oxygen homeostasis/hypoxia meeting. Cancer Research, 64, 3350–3356.

    PubMed  CAS  Google Scholar 

  9. Melillo, G., & Semenza, G. L. (2006). Meeting report: Exploiting the tumor microenvironment for therapeutics. Cancer Research, 66, 4558–4560.

    PubMed  CAS  Google Scholar 

  10. Sun, X., Kanwar, J. R., Leung, E., Lehnert, K., Wang, D., & Krissansen, G. W. (2001). Gene transfer of antisense hypoxia inducible factor-1 alpha enhances the therapeutic efficacy of cancer immunotherapy. Gene Therapy, 8, 638–645.

    PubMed  CAS  Google Scholar 

  11. Zhang, X., Kon, T., Wang, H., Li, F., Huang, Q., Rabbani, Z. N., et al. (2004). Enhancement of hypoxia-induced tumor cell death in vitro and radiation therapy in vivo by use of small interfering RNA targeted to hypoxia-inducible factor-1alpha. Cancer Research, 64, 8139–8142.

    PubMed  CAS  Google Scholar 

  12. Chang, Q., Qin, R., Huang, T., Gao, J., & Feng, Y. (2006). Effect of antisense hypoxia-inducible factor 1alpha on progression, metastasis, and chemosensitivity of pancreatic cancer. Pancreas, 32, 297–305.

    PubMed  CAS  Google Scholar 

  13. Li, L., Lin, X., Staver, M., Shoemaker, A., Semizarov, D., Fesik, S. W., et al. (2005). Evaluating hypoxia-inducible factor-1alpha as a cancer therapeutic target via inducible RNA interference in vivo. Cancer Research, 65, 7249–7258.

    PubMed  CAS  Google Scholar 

  14. Dachs, G. U., Patterson, A. V., Firth, J. D., Ratcliffe, P. J., Townsend, K. M., Stratford, I. J., et al. (1997). Targeting gene expression to hypoxic tumor cells. Nature Medicine, 3, 515–520.

    CAS  Google Scholar 

  15. Cuevas, Y., Hernandez-Alcoceba, R., Aragones, J., Naranjo-Suarez, S., Castellanos, M. C., Esteban, M. A., et al. (2003). Specific oncolytic effect of a new hypoxia-inducible factor-dependent replicative adenovirus on von Hippel-Lindau-defective renal cell carcinomas. Cancer Research, 63, 6877–6884.

    PubMed  CAS  Google Scholar 

  16. Brown, J. M. (1993). SR 4233 (tirapazamine): A new anticancer drug exploiting hypoxia in solid tumours. British Journal of Cancer, 67, 1163–1170.

    PubMed  CAS  Google Scholar 

  17. Peters, K. B., & Brown, J. M. (2002). Tirapazamine: A hypoxia-activated topoisomerase II poison. Cancer Research, 62, 5248–5253.

    PubMed  CAS  Google Scholar 

  18. von Pawel, J., von Roemeling, R., Gatzemeier, U., Boyer, M., Elisson, L. O., Clark, P., et al. (2000). Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: A report of the international CATAPULT I study group. Cisplatin and Tirapazamine in subjects with advanced previously untreated non-small-cell lung tumors. Journal of Clinical Oncology, 18, 1351–1359.

    Google Scholar 

  19. Williamson, S. K., Crowley, J. J., Lara, P. N., Jr., McCoy, J., Lau, D. H., Tucker, R. W., et al. (2005). Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. Journal of Clinical Oncology, 23, 9097–9104.

    PubMed  CAS  Google Scholar 

  20. Rischin, D., Peters, L., Fisher, R., Macann, A., Denham, J., Poulsen, M., et al. (2005). Tirapazamine, Cisplatin, and Radiation versus Fluorouracil, Cisplatin, and radiation in patients with locally advanced head and neck cancer: A randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). Journal of Clinical Oncology, 23, 79–87.

    PubMed  CAS  Google Scholar 

  21. Lemmon, M. J., van Zijl, P., Fox, M. E., Mauchline, M. L., Giaccia, A. J., Minton, N. P., et al. (1997). Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene Therapy, 4, 791–796.

    PubMed  CAS  Google Scholar 

  22. Liu, S. C., Minton, N. P., Giaccia, A. J., & Brown, J. M. (2002). Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Therapy, 9, 291–296.

    PubMed  CAS  Google Scholar 

  23. Dang, L. H., Bettegowda, C., Huso, D. L., Kinzler, K. W., & Vogelstein, B. (2001). Combination bacteriolytic therapy for the treatment of experimental tumors. Proceedings of the National Academy of Sciences of the United States of America, 98, 15155–15160.

    PubMed  CAS  Google Scholar 

  24. Cheong, I., Huang, X., Bettegowda, C., Diaz, L. A., Jr., Kinzler, K. W., Zhou, S., et al. (2006). A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Science, 314, 1308–1311.

    PubMed  CAS  Google Scholar 

  25. Schioppa, T., Uranchimeg, B., Saccani, A., Biswas, S. K., Doni, A., Rapisarda, A., et al. (2003). Regulation of the chemokine receptor CXCR4 by hypoxia. Journal of Experimental Medicine, 198, 1391–1402.

    PubMed  CAS  Google Scholar 

  26. Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., & Comoglio, P. M. (2003). Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell, 3, 347–361.

    PubMed  Google Scholar 

  27. Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q. T., et al. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440, 1222–1226.

    PubMed  CAS  Google Scholar 

  28. Ferrara, N. (2005). VEGF as a therapeutic target in cancer. Oncology, 69(Suppl 3), 11–16.

    PubMed  CAS  Google Scholar 

  29. Park, E. J., Kong, D., Fisher, R., Cardellina, J., Shoemaker, R. H., & Melillo, G. (2006). Targeting the PAS-a domain of HIF-1alpha for development of small molecule inhibitors of HIF-1. Cell Cycle, 5(16), 1847–1853.

    PubMed  CAS  Google Scholar 

  30. Zundel, W., Schindler, C., Haas-Kogan, D., Koong, A., Kaper, F., Chen, E., et al. (2000). Loss of PTEN facilitates HIF-1-mediated gene expression. Genes & Development, 14, 391–396.

    CAS  Google Scholar 

  31. Majumder, P. K., Febbo, P. G., Bikoff, R., Berger, R., Xue, Q., McMahon, L. M., et al. (2004). mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Medicine, 10, 594–601.

    CAS  Google Scholar 

  32. Thomas, G. V., Tran, C., Mellinghoff, I. K., Welsbie, D. S., Chan, E., Fueger, B., et al. (2006). Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Medicine, 12, 2–127.

    Google Scholar 

  33. Del Bufalo, D., Ciuffreda, L., Trisciuoglio, D., Desideri, M., Cognetti, F., Zupi, G., et al. (2006). Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Research, 66, 5549–5554.

    PubMed  Google Scholar 

  34. Calvani, M., Rapisarda, A., Uranchimeg, B., Shoemaker, R. H., & Melillo, G. (2005). Hypoxic induction of a HIF-1{alpha}-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells. Blood, 107, 2705–2712.

    PubMed  Google Scholar 

  35. Wan, X., Shen, N., Mendoza, A., Khanna, C., & Helman, L. J. (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.

    PubMed  CAS  Google Scholar 

  36. Zhong, H., Chiles, K., Feldser, D., Laughner, E., Hanrahan, C., Georgescu, M. M., et al. (2000). 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 Research, 60, 1541–1545.

    PubMed  CAS  Google Scholar 

  37. Pore, N., Jiang, Z., Gupta, A., Cerniglia, G., Kao, G. D., & Maity, A. (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.

    PubMed  CAS  Google Scholar 

  38. Peng, X., Karna, P., Cao, Z., Jiang, B., Zhou, M., & Yang, L. (2006). Cross-talk between epidermal growth factor receptor and HIF-1 signal pathways increases resistance to apoptosis by upregulating survivin gene expression. Journal of Biological Chemistry 281, 25903–25914.

    Google Scholar 

  39. Luwor, R. B., Lu, Y., Li, X., Mendelsohn, J., & Fan, Z. (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.

    PubMed  CAS  Google Scholar 

  40. Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C., & Semenza, G. L. (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.

    PubMed  CAS  Google Scholar 

  41. Koukourakis, M. I., Simopoulos, C., Polychronidis, A., Perente, S., Botaitis, S., Giatromanolaki, A., et al. (2003). The effect of trastuzumab/docatexel combination on breast cancer angiogenesis: Dichotomus effect predictable by the HIFI alpha/VEGF pre-treatment status? Anticancer Research, 23, 1673–1680.

    PubMed  CAS  Google Scholar 

  42. Mayerhofer, M., Valent, P., Sperr, W. R., Griffin, J. D., & Sillaber, C. (2002). BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood, 100, 3767–3775.

    PubMed  CAS  Google Scholar 

  43. Litz, J., & Krystal, G. W. (2006). Imatinib inhibits c-Kit-induced hypoxia-inducible factor-1alpha activity and vascular endothelial growth factor expression in small cell lung cancer cells. Molecular Cancer Therapy, 5, 1415–1422.

    CAS  Google Scholar 

  44. Cao, Z., Fang, J., Xia, C., Shi, X., & Jiang, B. H. (2004). trans-3,4,5′-Trihydroxystibene inhibits hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in human ovarian cancer cells. Clinical Cancer Research, 10, 5253–5263.

    PubMed  CAS  Google Scholar 

  45. Fang, J., Cao, Z., Chen, Y. C., Reed, E., & Jiang, B. H. (2004). 9-beta-D-arabinofuranosyl-2-fluoroadenine inhibits expression of vascular endothelial growth factor through hypoxia-inducible factor-1 in human ovarian cancer cells. Molecular Pharmacology, 66, 178–186.

    PubMed  CAS  Google Scholar 

  46. Fang, J., Xia, C., Cao, Z., Zheng, J. Z., Reed, E., & Jiang, B. H. (2005). Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB Journal, 19, 342–353.

    PubMed  CAS  Google Scholar 

  47. Pore, N., Gupta, A. K., Cerniglia, G. J., Jiang, Z., Bernhard, E. J., Evans, S. et al. (2006). Nelfinavir down-regulates hypoxia-inducible factor 1{alpha} and VEGF expression and increases tumor oxygenation: Implications for radiotherapy. Cancer Research, 66, 9252–9259.

    PubMed  CAS  Google Scholar 

  48. Tan, C., de Noronha, R. G., Roecker, A. J., Pyrzynska, B., Khwaja, F., Zhang, Z., et al. (2005). Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway. Cancer Research, 65, 605–612.

    PubMed  CAS  Google Scholar 

  49. Zhang, Q., Tang, X., Lu, Q., Zhang, Z., Rao, J., & Le, A. D. (2006). Green tea extract and (−)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1alpha protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells. Molecular Cancer Therapy, 5, 1227–1238.

    CAS  Google Scholar 

  50. Zhang, Q., Tang, X., Lu, Q. Y., Zhang, Z. F., Brown, J., & Le, A. D. (2005). Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells. Molecular Cancer Therapy, 4, 1465–1474.

    CAS  Google Scholar 

  51. Zhong, X. S., Zheng, J. Z., Reed, E., & Jiang, B. H. (2004). SU5416 inhibited VEGF and HIF-1alpha expression through the PI3K/AKT/p70S6K1 signaling pathway. Biochemical and Biophysical Research Communications, 324, 471–480.

    PubMed  CAS  Google Scholar 

  52. Pommier, Y. (2006). Topoisomerase I inhibitors: Camptothecins and beyond. Nature Reviews Cancer, 6, 789–802.

    PubMed  CAS  Google Scholar 

  53. Rapisarda, A., Uranchimeg, B., Scudiero, D. A., Selby, M., Sausville, E. A., Shoemaker, R. H., et al. (2002). Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Research, 62, 4316–4324.

    PubMed  CAS  Google Scholar 

  54. Rapisarda, A., Uranchimeg, B., Sordet, O., Pommier, Y., Shoemaker, R. H., & Melillo, G. (2004). Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: Mechanism and therapeutic implications. Cancer Research, 64, 1475–1482.

    PubMed  CAS  Google Scholar 

  55. Rapisarda, A., Zalek, J., Hollingshead, M., Braunschweig, T., Uranchimeg, B., Bonomi, C. A., et al. (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.

    PubMed  CAS  Google Scholar 

  56. Mabjeesh, N. J., Escuin, D., LaVallee, T. M., Pribluda, V. S., Swartz, G. M., Johnson, M. S. P., et al. (2003). 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell, 3, 363–375.

    PubMed  CAS  Google Scholar 

  57. Escuin, D., Kline, E. R., & Giannakakou, P. (2005). Both microtubule-stabilizing and microtubule-destabilizing drugs inhibit hypoxia-inducible factor-1alpha accumulation and activity by disrupting microtubule function. Cancer Research, 65, 9021–9028.

    PubMed  CAS  Google Scholar 

  58. Jung, Y. J., Isaacs, J. S., Lee, S., Trepel, J., & Neckers, L. (2003). Microtubule disruption utilizes an NFkappa B-dependent pathway to stabilize HIF-1alpha protein. Journal of Biological Chemistry, 278, 7445–7452.

    PubMed  CAS  Google Scholar 

  59. Kang, S. H., Cho, H. T., Devi, S., Zhang, Z., Escuin, D., Liang, Z., et al. (2006). Antitumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model. Cancer Research, 66, 11991–11997.

    PubMed  CAS  Google Scholar 

  60. Ricker, J. L., Chen, Z., Yang, X. P., Pribluda, V. S., Swartz, G. M., & Van Waes, C. (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.

    PubMed  CAS  Google Scholar 

  61. Isaacs, J. S., Jung, Y. J., Mimnaugh, E. G., Martinez, A., Cuttitta, F., & Neckers, L. M. (2002). Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. Journal of Biological Chemistry, 277, 29936–29944.

    PubMed  CAS  Google Scholar 

  62. Mabjeesh, N. J., Post, D. E., Willard, M. T., Kaur, B., Van Meir, E. G., Simons, J. W., et al. (2002). Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells. Cancer Research, 62, 2478–2482.

    PubMed  CAS  Google Scholar 

  63. Hur, E., Kim, H. H., Choi, S. M., Kim, J. H., Yim, S., Kwon, H. J., et al. (2002). Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1alpha/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol. Molecular Pharmacology, 62, 975–982.

    PubMed  CAS  Google Scholar 

  64. Kurebayashi, J., Otsuki, T., Kurosumi, M., Soga, S., Akinaga, S., & Sonoo, H. (2001). A radicicol derivative, KF58333, inhibits expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor, angiogenesis and growth of human breast cancer xenografts. Japanese Journal of Cancer Research, 92, 1342–1351.

    PubMed  CAS  Google Scholar 

  65. Han, J. Y., Oh, S. H., Morgillo, F., Myers, J. N., Kim, E., Hong, W. K., et al. (2005). Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer. Journal of the National Cancer Institute, 97, 1272–1286.

    PubMed  CAS  Google Scholar 

  66. Osada, M., Imaoka, S., & Funae, Y. (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.

    PubMed  CAS  Google Scholar 

  67. Kim, M. S., Kwon, H. J., Lee, Y. M., Baek, J. H., Jang, J. E., Lee, S. W., et al. (2001). Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nature Medicine, 7, 437–443.

    Google Scholar 

  68. Fath, D. M., Kong, X., Liang, D., Lin, Z., Chou, A., Jiang, Y., et al. (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.

    PubMed  CAS  Google Scholar 

  69. Kong, X., Lin, Z., Liang, D., Fath, D., Sang, N., & Caro, J. (2006). Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. Molecular and Cellular Biology, 26, 2019–2028.

    PubMed  CAS  Google Scholar 

  70. Qian, D. Z., Kachhap, S. K., Collis, S. J., Verheul, H. M. W., Carducci, M. A., Atadja, P., et al. (2006). Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1{alpha}. Cancer Research, 66, 8814–8821.

    PubMed  CAS  Google Scholar 

  71. Chun, Y. S., Yeo, E. J., & Park, J. W. (2004). Versatile pharmacological actions of YC-1: Anti-platelet to anticancer. Cancer Letters, 207, 1–7.

    PubMed  CAS  Google Scholar 

  72. Chun, Y. S., Yeo, E. J., Choi, E., Teng, C. M., Bae, J. M., Kim, M. S., et al. (2001). Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochemical Pharmacology, 61, 947–954.

    PubMed  CAS  Google Scholar 

  73. Yeo, E. J., Chun, Y. S., Cho, Y. S., Kim, J., Lee, J. C., Kim, M. S., et al. (2003). YC-1: A potential anticancer drug targeting hypoxia-inducible factor 1. Journal of the National Cancer Institute, 95, 516–525.

    PubMed  CAS  Google Scholar 

  74. Kim, H. L., Yeo, E. J., Chun, Y. S., & Park, J. W. (2006). A domain responsible for HIF-1alpha degradation by YC-1, a novel anticancer agent. International Journal of Oncology, 29, 255–260.

    PubMed  CAS  Google Scholar 

  75. Welsh, S., Williams, R., Kirkpatrick, L., Paine-Murrieta, G., & Powis, G. (2004). Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Molecular Cancer Therapy, 3, 233–244.

    CAS  Google Scholar 

  76. Welsh, S. J., Bellamy, W. T., Briehl, M. M., & Powis, G. (2002). 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. Cancer Research, 62, 5089–5095.

    PubMed  CAS  Google Scholar 

  77. Welsh, S. J., Williams, R. R., Birmingham, A., Newman, D. J., Kirkpatrick, D. L., & Powis, G. (2003). The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation. Molecular Cancer Therapy, 2, 235–243.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  79. Chau, N. M., Rogers, P., Aherne, W., Carroll, V., Collins, I., McDonald, E., et al. (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.

    PubMed  CAS  Google Scholar 

  80. Jones, M. K., Szabo, I. L., Kawanaka, H., Husain, S. S., & Tarnawski, A. S. (2002). von Hippel Lindau tumor suppressor and HIF-1alpha: New targets of NSAIDs inhibition of hypoxia-induced angiogenesis. FASEB Journal, 16, 264–266.

    PubMed  CAS  Google Scholar 

  81. Palayoor, S. T., Tofilon, P. J., & Coleman, C. N. (2003). Ibuprofen-mediated reduction of hypoxia-inducible factors HIF-1alpha and HIF-2alpha in prostate cancer cells. Clinical Cancer Research, 9, 3150–3157.

    PubMed  CAS  Google Scholar 

  82. Zhong, H., Willard, M., & Simons, J. (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.

    CAS  Google Scholar 

  83. Knowles, H. J., Raval, R. R., Harris, A. L., & Ratcliffe, P. J. (2003). Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Research, 63, 1764–1768.

    PubMed  CAS  Google Scholar 

  84. Melillo, G., Sausville, E. A., Cloud, K., Lahusen, T., Varesio, L., & Senderowicz, A. M. (1999). Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes. Cancer Research, 59, 5433–5437.

    PubMed  CAS  Google Scholar 

  85. Newcomb, E. W., Ali, M. A., Schnee, T., Lan, L., Lukyanov, Y., Fowkes, M., et al. (2005). Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1alpha expression in human glioma cells by a proteasome-independent pathway: Implications for in vivo therapy. Journal of Neuro-Oncology, 7, 225–235.

    CAS  Google Scholar 

  86. Buchler, P., Reber, H. A., Buchler, M. W., Friess, H., Lavey, R. S., & Hines, O. J. (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.

    PubMed  CAS  Google Scholar 

  87. Dervan, P. B., & Edelson, B. S. (2003). Recognition of the DNA minor groove by pyrrole-imidazole polyamides. Current Opinion in Structural Biology, 13, 284–299.

    PubMed  CAS  Google Scholar 

  88. Olenyuk, B. Z., Zhang, G. J., Klco, J. M., Nickols, N. G., Kaelin, W. G., Jr., & Dervan, P. B. (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.

    PubMed  CAS  Google Scholar 

  89. Nickols, N. G., Jacobs, C. S., Farkas, M. E., & Dervan, P. B. (2007). Improved nuclear localization of DNA-binding polyamides. Nucleic Acids Research, 35(2), 363–370.

    PubMed  CAS  Google Scholar 

  90. Van Dyke, M. M., & Dervan, P. B. (1984). Echinomycin binding sites on DNA. Science, 225, 1122–1127.

    PubMed  Google Scholar 

  91. Kong, D., Park, E. J., Stephen, A. G., Calvani, M., Cardellina, J. H., Monks, A., et al. (2005). Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Research, 65, 9047–9055.

    PubMed  CAS  Google Scholar 

  92. Kung, A. L., Wang, S., Klco, J. M., Kaelin, W. G., & Livingston, D. M. (2000). Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nature Medicine, 6, 1335–1340.

    CAS  Google Scholar 

  93. Kung, A. L., Zabludoff, S. D., France, D. S., Freedman, S. J., Tanner, E. A., Vieira, A., et al. (2004). Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell, 6, 33–43.

    PubMed  CAS  Google Scholar 

  94. Kaluz, S., Kaluzova, M., & Stanbridge, E. J. (2006). Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain. Molecular and Cellular Biology, 26, 5895–5907.

    PubMed  CAS  Google Scholar 

  95. Yeo, E. J., Ryu, J. H., Cho, Y. S., Chun, Y. S., Huang, L. E., Kim, M. S., et al. (2006). Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1. Blood, 107, 916–923.

    PubMed  CAS  Google Scholar 

  96. Nagle, D. G., & Zhou, Y. D. (2006). Natural product-based inhibitors of hypoxia-inducible factor-1 (HIF-1). Current Drugs Targets, 7, 355–369.

    CAS  Google Scholar 

  97. Dai, J., Fishback, J. A., Zhou, Y. D., & Nagle, D. G. (2006). Sodwanone and Yardenone Triterpenes from a South African species of the marine sponge Axinella inhibit Hypoxia-Inducible Factor-1 (HIF-1) activation in both breast and prostate tumor cells. Journal of Natural Products, 69, 1715–1720.

    PubMed  CAS  Google Scholar 

  98. Hodges, T. W., Hossain, C. F., Kim, Y. P., Zhou, Y. D., & Nagle, D. G. (2004). Molecular-targeted antitumor agents: The Saururus cernuus dineolignans manassantin B and 4-O-demethylmanassantin B are potent inhibitors of hypoxia-activated HIF-1. Journal of Natural Products, 67, 767–771.

    PubMed  CAS  Google Scholar 

  99. Mohammed, K. A., Hossain, C. F., Zhang, L., Bruick, R. K., Zhou, Y. D., & Nagle, D. G. (2004). Laurenditerpenol, a new diterpene from the tropical marine alga Laurenciaintricata that potently inhibits HIF-1 mediated hypoxic signaling in breast tumor cells. Journal of Natural Products, 67, 2002–2007.

    PubMed  CAS  Google Scholar 

  100. Zhou, Y. D., Kim, Y. P., Mohammed, K. A., Jones, D. K., Muhammad, I., Dunbar, D. C., et al. (2005). Terpenoid tetrahydroisoquinoline alkaloids emetine, klugine, and isocephaeline inhibit the activation of hypoxia-inducible factor-1 in breast tumor cells. Journal of Natural Products, 68, 947–950.

    PubMed  CAS  Google Scholar 

  101. Choi, H., Chun, Y. S., Kim, S. W., Kim, M. S., & Park, J. W. (2006). Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: A mechanism of tumor growth inhibition. Molecular Pharmacology, 70, 1664–1671.

    PubMed  CAS  Google Scholar 

  102. Lin, S., Tsai, S. C., Lee, C. C., Wang, B. W., Liou, J. Y., & Shyu, K. G. (2004). Berberine inhibits HIF-1alpha expression via enhanced proteolysis. Molecular Pharmacology, 66, 612–619.

    PubMed  CAS  Google Scholar 

  103. Li, M. H., Miao, Z. H., Tan, W. F., Yue, J. M., Zhang, C., Lin, L. P., et al. (2004). Pseudolaric acid B inhibits angiogenesis and reduces hypoxia-inducible factor 1alpha by promoting proteasome-mediated degradation. Clinical Cancer Research, 10, 8266–8274.

    PubMed  CAS  Google Scholar 

  104. Cai, X. F., Jin, X., Lee, D., Yang, Y. T., Lee, K., Hong, Y. S., et al. (2006). Phenanthroquinolizidine alkaloids from the roots of Boehmeria pannosa potently inhibit Hypoxia-Inducible Factor-1 in AGS human gastric cancer cells. Journal of Natural Products, 69, 1095–1097.

    PubMed  CAS  Google Scholar 

  105. Hasebe, Y., Egawa, K., Yamazaki, Y., Kunimoto, S., Hirai, Y., Ida, Y., et al. (2003). Specific inhibition of hypoxia-Inducible Factor (HIF)-1 alpha activation and of vascular endothelial growth factor (VEGF) production by flavonoids. Biological & Pharmaceutical Bulletin, 26, 1379–1383.

    CAS  Google Scholar 

  106. Li, L., Lin, X., Shoemaker, A. R., Albert, D. H., Fesik, S. W., & Shen, Y. (2006). Hypoxia-Inducible Factor-1 inhibition in combination with temozolomide treatment exhibits robust antitumor efficacy in vivo. Clinical Cancer Research, 12, 4747–4754.

    PubMed  CAS  Google Scholar 

  107. Brown, L. M., Cowen, R. L., Debray, C., Eustace, A., Erler, J. T., Sheppard, F. C., et al. (2005). Reversing hypoxic cell chemoresistance in vitro using genetic and small molecule approaches targeting Hypoxia Inducible Factor. Molecular Pharmacology, 69, 411–418.

    PubMed  Google Scholar 

  108. Moeller, B. J., Cao, Y., Li, C. Y., & Dewhirst, M. W. (2004). Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules. Cancer Cell, 5, 429–441.

    PubMed  CAS  Google Scholar 

  109. Moeller, B. J., Dreher, M. R., Rabbani, Z. N., Schroeder, T., Cao, Y., Li, C. Y., et al. (2005). Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell, 8, 99–110.

    PubMed  CAS  Google Scholar 

  110. Mie, L. Y., Kim, S. H., Kim, H. S., Jin, S. M., Nakajima, H., Jeong, K. H., et al. (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.

    Google Scholar 

  111. Jones, D. T., Pugh, C. W., Wigfield, S., Stevens, M. F. G., & Harris, A. L. (2006). Novel thioredoxin inhibitors paradoxically increase Hypoxia-Inducible Factor-{alpha} expression but decrease functional transcriptional activity, DNA binding, and degradation. Clinical Cancer Research, 12, 5384–5394.

    PubMed  CAS  Google Scholar 

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  1. Developmental Therapeutics Program, SAIC Frederick, Inc, National Cancer Institute, Frederick, MD, 21702, USA

    Giovanni Melillo

  2. Tumor Hypoxia Laboratory, National Cancer Institute, Frederick, Bldg 432, Rm 218, MD, 21702-1201, USA

    Giovanni Melillo

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Melillo, G. Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26, 341–352 (2007). https://doi.org/10.1007/s10555-007-9059-x

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