This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rapisarda, A. Articles by Melillo, G. Search for Related Content PubMed PubMed Citation Articles by Rapisarda, A. Articles by Melillo, G.

Topoisomerase I-Mediated Inhibition of Hypoxia-Inducible Factor 1

Mechanism and Therapeutic Implications

¹ Developmental Therapeutics Program, ² Tumor Hypoxia Laboratory, Science Applications International Corporation–Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland, and ³ Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

We have shown previously that the camptothecin analogue topotecan (TPT), a topoisomerase I (Top 1) poison, inhibits hypoxia-inducible factor 1 (HIF-1) transcriptional activity and HIF-1 protein accumulation in hypoxia-treated U251 human glioma cells. In this article, we demonstrate that TPT does not affect HIF-1 protein half-life or mRNA accumulation but inhibits its translation. In addition, we demonstrate that Top 1 is required for the inhibition of HIF-1 protein accumulation by TPT as shown by experiments performed using camptothecin-resistant cell lines with known Top 1 alterations. Experiments performed with aphidicolin indicated that TPT inhibited HIF-1 protein accumulation in the absence of DNA replication. DNA-damaging agents, such as ionizing radiation and doxorubicin, did not affect HIF-1 protein accumulation. Ongoing transcription was essential for the inhibition of HIF-1 protein accumulation by TPT. Our results demonstrate the existence of a novel pathway connecting Top 1-dependent signaling events and the regulation of HIF-1 protein expression and function. In addition, our findings dissociate the cytotoxic activity of TPT from the inhibition of the HIF-1 pathway and raise the possibility of novel clinical applications of TPT aimed at targeting HIF-1-dependent responses.

This article has been cited by other articles:

				L. Baranello, D. Bertozzi, M. V. Fogli, Y. Pommier, and G. Capranico DNA topoisomerase I inhibition by camptothecin induces escape of RNA polymerase II from promoter-proximal pause site, antisense transcription and histone acetylation at the human HIF-1{alpha} gene locus Nucleic Acids Res., November 9, 2009; (2009) gkp817v2. [Abstract] [Full Text] [PDF]

				P. Hersey, R. N. Watts, X. D. Zhang, and J. Hackett Metabolic Approaches to Treatment of Melanoma Clin. Cancer Res., November 1, 2009; 15(21): 6490 - 6494. [Abstract] [Full Text] [PDF]

				P. Sapra, P. Kraft, M. Mehlig, J. Malaby, H. Zhao, L. M. Greenberger, and I. D. Horak Marked therapeutic efficacy of a novel polyethylene glycol-SN38 conjugate, EZN-2208, in xenograft models of B-cell non-Hodgkin's lymphoma Haematologica, October 1, 2009; 94(10): 1456 - 1459. [Abstract] [Full Text] [PDF]

				A. Rapisarda, M. Hollingshead, B. Uranchimeg, C. A. Bonomi, S. D. Borgel, J. P. Carter, B. Gehrs, M. Raffeld, R. J. Kinders, R. Parchment, et al. Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition Mol. Cancer Ther., July 1, 2009; 8(7): 1867 - 1877. [Abstract] [Full Text] [PDF]

				K. Gravdal, O. J. Halvorsen, S. A. Haukaas, and L. A. Akslen Proliferation of Immature Tumor Vessels Is a Novel Marker of Clinical Progression in Prostate Cancer Cancer Res., June 1, 2009; 69(11): 4708 - 4715. [Abstract] [Full Text] [PDF]

				K. Burkitt, S. Y. Chun, D. T. Dang, and L. H. Dang Targeting both HIF-1 and HIF-2 in human colon cancer cells improves tumor response to sunitinib treatment Mol. Cancer Ther., May 1, 2009; 8(5): 1148 - 1156. [Abstract] [Full Text] [PDF]

				E. Pencreach, E. Guerin, C. Nicolet, I. Lelong-Rebel, A.-C. Voegeli, P. Oudet, A. K. Larsen, M.-P. Gaub, and D. Guenot 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-1{alpha} Axis Clin. Cancer Res., February 15, 2009; 15(4): 1297 - 1307. [Abstract] [Full Text] [PDF]

				M. Puppo, F. Battaglia, C. Ottaviano, S. Delfino, D. Ribatti, L. Varesio, and M. C. Bosco Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1{alpha} and -2{alpha} Mol. Cancer Ther., July 1, 2008; 7(7): 1974 - 1984. [Abstract] [Full Text] [PDF]

				P. Sapra, H. Zhao, M. Mehlig, J. Malaby, P. Kraft, C. Longley, L. M. Greenberger, and I. D. Horak Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11-Refractory Model Clin. Cancer Res., March 15, 2008; 14(6): 1888 - 1896. [Abstract] [Full Text] [PDF]

				M. Calvani, D. Trisciuoglio, C. Bergamaschi, R. H. Shoemaker, and G. Melillo Differential Involvement of Vascular Endothelial Growth Factor in the Survival of Hypoxic Colon Cancer Cells Cancer Res., January 1, 2008; 68(1): 285 - 291. [Abstract] [Full Text] [PDF]

				A. Rapisarda and G. Melillo HIF-1 Inhibitors: Novel Opportunities for Cancer Therapy ASCO Educational Book, January 1, 2008; 2008(1): 543 - 547. [Abstract] [Full Text] [PDF]

				L. Martin and R. Schilder Novel Approaches in Advancing the Treatment of Epithelial Ovarian Cancer: The Role of Angiogenesis Inhibition J. Clin. Oncol., July 10, 2007; 25(20): 2894 - 2901. [Abstract] [Full Text] [PDF]

				D. A. Rempe, K. M. Lelli, G. Vangeison, R. S. Johnson, and H. J. Federoff In Cultured Astrocytes, p53 and MDM2 Do Not Alter Hypoxia-inducible Factor-1{alpha} Function Regardless of the Presence of DNA Damage J. Biol. Chem., June 1, 2007; 282(22): 16187 - 16201. [Abstract] [Full Text] [PDF]

				J. L. Martin and R. C. Baxter Expression of Insulin-Like Growth Factor Binding Protein-2 by MCF-7 Breast Cancer Cells Is Regulated through the Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Pathway Endocrinology, May 1, 2007; 148(5): 2532 - 2541. [Abstract] [Full Text] [PDF]

				M. Dallas, H. E. Boycott, L. Atkinson, A. Miller, J. P. Boyle, H. A. Pearson, and C. Peers Hypoxia Suppresses Glutamate Transport in Astrocytes J. Neurosci., April 11, 2007; 27(15): 3946 - 3955. [Abstract] [Full Text] [PDF]

				M. Creighton-Gutteridge, J. H. Cardellina II, A. G. Stephen, A. Rapisarda, B. Uranchimeg, K. Hite, W. A. Denny, R. H. Shoemaker, and G. Melillo Cell Type-Specific, Topoisomerase II-Dependent Inhibition of Hypoxia-Inducible Factor-1{alpha} Protein Accumulation by NSC 644221 Clin. Cancer Res., February 1, 2007; 13(3): 1010 - 1018. [Abstract] [Full Text] [PDF]

				W. M. Linehan, P. A. Pinto, R. Srinivasan, M. Merino, P. Choyke, L. Choyke, J. Coleman, J. Toro, G. Glenn, C. Vocke, et al. Identification of the Genes for Kidney Cancer: Opportunity for Disease-Specific Targeted Therapeutics Clin. Cancer Res., January 15, 2007; 13(2): 671s - 679s. [Abstract] [Full Text] [PDF]

				O. Iliopoulos Molecular Biology of Renal Cell Cancer and the Identification of Therapeutic Targets J. Clin. Oncol., December 10, 2006; 24(35): 5593 - 5600. [Abstract] [Full Text] [PDF]

				D. T. Jones and A. L. Harris Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding. Mol. Cancer Ther., September 1, 2006; 5(9): 2193 - 2202. [Abstract] [Full Text] [PDF]

				G. Melillo Inhibiting Hypoxia-Inducible Factor 1 for Cancer Therapy Mol. Cancer Res., September 1, 2006; 4(9): 601 - 605. [Abstract] [Full Text] [PDF]

				V. A. Carroll and M. Ashcroft Role of Hypoxia-Inducible Factor (HIF)-1{alpha} versus HIF-2{alpha} 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 Res., June 15, 2006; 66(12): 6264 - 6270. [Abstract] [Full Text] [PDF]

				M. F. McCarty and K. I. Block Toward a Core Nutraceutical Program for Cancer Management Integr Cancer Ther, June 1, 2006; 5(2): 150 - 171. [Abstract] [PDF]

				M. Calvani, A. Rapisarda, B. Uranchimeg, R. H. Shoemaker, and G. Melillo Hypoxic induction of an HIF-1{alpha}-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells Blood, April 1, 2006; 107(7): 2705 - 2712. [Abstract] [Full Text] [PDF]

				D. Kong, E. J. Park, A. G. Stephen, M. Calvani, J. H. Cardellina, A. Monks, R. J. Fisher, R. H. Shoemaker, and G. Melillo Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity Cancer Res., October 1, 2005; 65(19): 9047 - 9055. [Abstract] [Full Text] [PDF]

				C. Hose, G. Kaur, E. A. Sausville, and A. Monks Transcriptional Profiling Identifies Altered Intracellular Labile Iron Homeostasis as a Contributing Factor to the Toxicity of Adaphostin: Decreased Vascular Endothelial Growth Factor Secretion Is Independent of Hypoxia-Inducible Factor-1 Regulation Clin. Cancer Res., September 1, 2005; 11(17): 6370 - 6381. [Abstract] [Full Text] [PDF]

				K. Beppu, K. Nakamura, W. M. Linehan, A. Rapisarda, and C. J. Thiele Topotecan Blocks Hypoxia-Inducible Factor-1{alpha} and Vascular Endothelial Growth Factor Expression Induced by Insulin-Like Growth Factor-I in Neuroblastoma Cells Cancer Res., June 1, 2005; 65(11): 4775 - 4781. [Abstract] [Full Text] [PDF]

				N.-M. Chau, P. Rogers, W. Aherne, V. Carroll, I. Collins, E. McDonald, P. Workman, and M. Ashcroft Identification of Novel Small Molecule Inhibitors of Hypoxia-Inducible Factor-1 That Differentially Block Hypoxia-Inducible Factor-1 Activity and Hypoxia-Inducible Factor-1{alpha} Induction in Response to Hypoxic Stress and Growth Factors Cancer Res., June 1, 2005; 65(11): 4918 - 4928. [Abstract] [Full Text] [PDF]

				G. J. Kelloff, J. M. Hoffman, B. Johnson, H. I. Scher, B. A. Siegel, E. Y. Cheng, B. D. Cheson, J. O'Shaughnessy, K. Z. Guyton, D. A. Mankoff, et al. Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development Clin. Cancer Res., April 15, 2005; 11(8): 2785 - 2808. [Abstract] [Full Text] [PDF]

				C. Tan, R. G. de Noronha, A. J. Roecker, B. Pyrzynska, F. Khwaja, Z. Zhang, H. Zhang, Q. Teng, A. C. Nicholson, P. Giannakakou, et al. Identification of a Novel Small-Molecule Inhibitor of the Hypoxia-Inducible Factor 1 Pathway Cancer Res., January 15, 2005; 65(2): 605 - 612. [Abstract] [Full Text] [PDF]

				A. Rapisarda, J. Zalek, M. Hollingshead, T. Braunschweig, B. Uranchimeg, C. A. Bonomi, S. D. Borgel, J. P. Carter, S. M. Hewitt, R. H. Shoemaker, et al. Schedule-dependent Inhibition of Hypoxia-inducible Factor-1{alpha} Protein Accumulation, Angiogenesis, and Tumor Growth by Topotecan in U251-HRE Glioblastoma Xenografts Cancer Res., October 1, 2004; 64(19): 6845 - 6848. [Abstract] [Full Text] [PDF]

				A. J. Giaccia, M. C. Simon, and R. Johnson The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease Genes & Dev., September 15, 2004; 18(18): 2183 - 2194. [Abstract] [Full Text] [PDF]

				W. M. Linehan, J. Vasselli, R. Srinivasan, M. M. Walther, M. Merino, P. Choyke, C. Vocke, L. Schmidt, J. S. Isaacs, G. Glenn, et al. Genetic Basis of Cancer of the Kidney: Disease-Specific Approaches to Therapy Clin. Cancer Res., September 15, 2004; 10(18): 6282S - 6289S. [Abstract] [Full Text] [PDF]

				W. G. Kaelin Jr. The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer Clin. Cancer Res., September 15, 2004; 10(18): 6290S - 6295S. [Abstract] [Full Text] [PDF]

				G. Powis and L. Kirkpatrick Hypoxia inducible factor-1{alpha} as a cancer drug target Mol. Cancer Ther., May 1, 2004; 3(5): 647 - 654. [Abstract] [Full Text] [PDF]