Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline

Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo. (C) 2015 AACR.