Overcoming Drug Resistance by Targeting Cancer Bioenergetics with an Activatable Prodrug.

Nearly without exception, all known cancer chemotherapeutics elicit a resistance response over time. The resulting resistance is correlated with poor clinical outcomes. Here, we report an approach to overcoming resistance through reprogramming oncogene-directed alterations in mitochondrial metabolism before drug activation while simultaneously circumventing drug efflux pumps. Conjugate C1 increases cancer cell apoptosis and inhibits regrowth of drug-resistant tumors, as inferred from efficacy studies carried out in human cancer cells and in Dox-resistant xenograft tumor models. It also displays minimal whole-animal toxicity. These benefits are ascribed to an ability to evade chemoresistance by switching cancer cell metabolism back to normal mitochondrial oxidative phosphorylation while helping target the active Dox to first the mitochondrion and then the nucleus.