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 Cl 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 chemo-resistance by switching cancer cell metabolism back to normal mitochondrial oxidative phosphorylation while helping target the active Dox to first the mito-chondrion and then the nucleus.