Manipulation of the apoptotic pathway has long been recognized as an effective strategy for the eradication of cancer cells. This work targets the labile zinc pool, a physiological inhibitor of apoptosis utilizing a small molecule, PAC-1. Labile zinc inhibits the conversion of procaspase-3 to caspase-3, preventing the activation of this key apoptotic executioner.  Aiming to harness the potential of active caspases for the selective treatment of cancer, we developed PAC-1, a mild zinc chelator (Kd ~ 42 nM) to facilitate caspase activation. PAC-1 rapidly enters cells, elicits a reduction in the labile zinc pool, induces apoptotic cell death, and has shown efficacy in multiple animal models of cancer.  Recently we have used PAC-1 to prime cells for more effective treatment by targeted and conventional cancer chemotherapeutics.  By relieving the zinc-mediated inhibition of the procaspases, cancer cells are more responsive to cytotoxins and cell death signals. This synergistic potential and increase in potency, driven by the primed and uninhibited procaspase-3, has been demonstrated mechanistically, shown in cell culture, and validated in animal models of cancer.  Thus, PAC-1, a well-tolerated compound with significant single agent anticancer activity, has the capacity to increase the efficacy of a diverse panel of standard-of-care chemotherapeutics. Procaspase priming may therefore serve as a general strategy to increase the apoptotic potential of the cell and be a general method for potentiation of chemotherapeutic agents in vivo.

Small molecule mediated relief of procaspase inhibition enhances the potency of cancer chemotherapeutics

246th National Meeting (2013)

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