Cell Type–Specific, Topoisomerase II–Dependent Inhibition of Hypoxia-Inducible Factor-1α Protein Accumulation by NSC 644221
| Autor: | William A. Denny, Badarch Uranchimeg, Andrew G. Stephen, Annamaria Rapisarda, Giovanni Melillo, Robert H. Shoemaker, Mark Creighton-Gutteridge, John H. Cardellina, Karen M. Hite |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Small interfering RNA Time Factors Antineoplastic Agents Biology Transfection chemistry.chemical_compound Cell Line Tumor Neoplasms MG132 Humans Gene silencing Polycyclic Compounds RNA Messenger Enzyme Inhibitors RNA Small Interfering Luciferases Topoisomerase Temperature Hypoxia-Inducible Factor 1 alpha Subunit Amides Cell biology Gene Expression Regulation Neoplastic DNA Topoisomerases Type II Models Chemical nervous system Oncology Biochemistry Hypoxia-inducible factors chemistry Cell culture Cancer cell biology.protein |
| Zdroj: | Clinical Cancer Research. 13:1010-1018 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-06-2301 |
| Popis: | Purpose: The discovery and development of small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1) is an attractive, yet challenging, strategy for the development of new cancer therapeutic agents. Here, we report on a novel tricyclic carboxamide inhibitor of HIF-1α, NSC 644221. Experimental Design: We investigated the mechanism by which the novel compound NSC 644221 inhibited HIF-1α. Results: NSC 644221 inhibited HIF-1–dependent, but not constitutive, luciferase expression in U251-HRE and U251-pGL3 cells, respectively, as well as hypoxic induction of vascular endothelial growth factor mRNA expression in U251 cells. HIF-1α, but not HIF-1β, protein expression was inhibited by NSC 644221 in a time- and dose-dependent fashion. Interestingly, NSC 644221 was unable to inhibit HIF-1α protein accumulation in the presence of the proteasome inhibitors MG132 or PS341, yet it did not directly affect the degradation of HIF-1α as shown by experiments done in the presence of cyclohexamide or pulse-chase labeling using [35S]methionine. In contrast, NSC 644221 decreased the rate of HIF-1α translation relative to untreated controls. Silencing of topoisomerase (topo) IIα, but not topo I, by specific small interfering RNA completely blocked the ability of NSC 644221 to inhibit HIF-1α. The data presented show that topo II is required for the inhibition of HIF-1α by NSC 644221. Furthermore, although NSC 644221 induced p21 expression, γH2A.X, and G2-M arrest in the majority of cell lines tested, it only inhibited HIF-1α in a distinct subset of cells, raising the possibility of pathway-specific “resistance” to HIF-1 inhibition in cancer cells. Conclusions: NSC 644221 is a novel HIF-1 inhibitor with potential for use as both an analytic tool and a therapeutic agent. Our data provide a strong rationale for pursuing the preclinical development of NSC 644221 as a HIF-1 inhibitor. |
| Databáze: | OpenAIRE |
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