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Reversing Hypoxic Cell Chemoresistance in Vitro Using Genetic and Small Molecule Approaches Targeting Hypoxia Inducible Factor-1

Experimental Oncology, School of Pharmacy and Pharmaceutical Sciences (R.L.C., C.D., A.E., F.C.D.S., C.A.P., I.J.S., K.J.W.) and Maternal and Foetal Health Research Centre, St. Mary's Hospital (L.M.B.), University of Manchester, Manchester, United Kingdom; and Stanford University School of Medicine, Department of Radiation Oncology, Stanford, California (J.T.E.)

The resistance of hypoxic cells to conventional chemotherapy is well documented. Using both adenovirus-mediated gene delivery and small molecules targeting hypoxia-inducible factor-1 (HIF-1), we evaluated the impact of HIF-1 inhibition on the sensitivity of hypoxic tumor cells to etoposide. The genetic therapy exploited a truncated HIF-1 protein that acts as a dominant-negative HIF-1 (HIF-1-no-TAD). Its functionality was validated in six human tumor cell lines using HIF-1 reporter assays. An EGFP-fused protein demonstrated that the dominant-negative HIF-1 was nucleus-localized and constitutively expressed irrespective of oxygen tension. The small molecules studied were quinocarmycin monocitrate (KW2152), its analog 7-cyanoquinocarcinol (DX-52-1), and topotecan. DX-52-1 and topotecan have been previously established as HIF-1 inhibitors. HT1080 and HCT116 cells were treated with either AdHIF-1-no-TAD or nontoxic concentrations (0.1 µM; <IC₁₀) of KW2152 and DX-52-1 and exposed to etoposide in air or anoxia (<0.01% oxygen). Topotecan inhibited HIF-1 activity only at cytotoxic concentrations and was not used in the combination study. Etoposide IC₅₀ values in anoxia were 3-fold higher than those in air for HT1080 (2.2 ± 0.3 versus 0.7 ± 0.2 µM) and HCT116 (9 ± 4 versus 3 ± 2 µM) cells. KW2152 and DX-52-1 significantly reduced the anoxic etoposide IC₅₀ in HT1080 cells, whereas only KW2152 yielded sensitization in HCT116 cells. In contrast, AdHIF-1-no-TAD (multiplicity of infection 50) ablated the anoxic resistance in both cell lines (IC₅₀ values: HT1080, 0.7 ± 0.04 µM; HCT116, 3 ± 1 µM). HIF-1-no-TAD expression inhibited HIF-1-mediated down-regulation of the proapoptotic protein Bid under anoxia. These data support the potential development of HIF-1 targeted approaches in combination with chemotherapy, where hypoxic cell resistance contributes to treatment failure.

Address correspondence to: Dr. Kaye J. Williams, Experimental Oncology, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PL, UK. E-mail: kaye.williams{at}manchester.ac.uk

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