Overcoming Drug Resistance by Targeting Cancer Bioenergetics with an Activatable Prodrug

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author Jong Seung Kim
Homepage http://orgchem.korea.ac.kr/
journal Chem (Cell press) DOI:https://doi.org/10.1016/j.chempr.2018.08.002


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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 a new approach to overcoming resistance that involves reprogramming oncogene-directed alterations in mitochondrial metabolism prior to 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.



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