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Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor

Authors' Affiliations: ¹ Drug Discovery Support, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut and ² Department of Surgery, ³ Division of Pharmaceutics, and ⁴ Departments of Pathology, and ⁵ Radiology, Ohio State University, Columbus, Ohio

Requests for reprints: Duxin Sun, Division of Pharmaceutics, School of Pharmacy, Ohio State University. 500 W. 12th Avenue, Columbus, OH 43210. Phone: 614-292-4381; Fax: 614-292-7766; E-mail: sun.176{at}osu.edu.

Purpose: We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production.

Experimental Design: The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase II inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging.

Results: Hypoxia enhanced HIF-1 expression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven- to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17- to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition.

Conclusions: The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapy-resistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.