Synergistic anti-pancreatic tumor effect by simultaneously targeting hypoxic cancer cells with hsp90 inhibitor and glycolysis inhibitor

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Purposes: To examine the synergistic anti-pancreatic cancer effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and blockade of energy production.
 Experimental design: The anticancer effects of a HSP90 inhibitor (geldanamycin, GA) 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 GA and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a non-invasive dynamic-contrast-enhanced magnetic resonance imaging (DCEMRI).
 Results: Hypoxia enhanced HIF-1α expression by 11-fold in pancreatic cancer cells and HSP90 inhibitor exhibited 7 to 8-fold higher anticancer effect in hypoxia compared to normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized GA 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.
 Conclusion: 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 chemo-resistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.