Overcoming hypoxia-induced apoptotic resistance through combinatorial inhibition of GSK-3β and CDK1

Tumor hypoxia is an inherent impediment to cancer treatment that is both clinically significant and problematic. In this study, we performed a cell-based screen to identify small molecules that could reverse the apoptotic resistance of hypoxic cancer cells. Among the compounds we identified were a structurally-related group that sensitized hypoxic cancer cells to apoptosis by inhibiting the kinases GSK-3β and CDK1. Combinatorial inhibition of these proteins in hypoxic cancer cells and tumors increased levels of c-Myc and decreased expression of c-IAP2 and the central hypoxia response regulator Hif-1α. In mice, these compounds augmented the hypoxic tumor cell death induced by cytotoxic chemotherapy, blocking angiogenesis and tumor growth. Taken together, our findings suggest that combinatorial inhibition of GSK-3β and CDK1 augment the apoptotic sensitivity of hypoxic tumors, and they offer preclinical validation of a novel and readily translatable strategy to improve cancer therapy.