Overcoming Drug Resistance by Targeting Cancer Bioenergetics with an Activatable Prodrug

Amit Sharma, Min Goo Lee, Hu Shi, Miae Won, Jonathan F. Arambula, Jonathan L. Sessler, Jin Yong Lee, Sung-Gil Chi, Jong Seung Kim

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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. Drug resistance is a particularly pernicious feature of modern cancer chemotherapy. In many instances, drug resistance is correlated with aberrant metabolic adaptations that favor aerobic glycolysis over oxidative phosphorylation. To date, efforts have been made to overcome resistance by targeting the metabolic changes associated with resistance, albeit with limited effect. The hypothesis underlying the present work is that a multipronged strategy might be more effective. As detailed in this study, we have found that a rationally designed conjugate that both restores oxidative phosphorylation and permits the targeted delivery of doxorubicin (a known anticancer agent) to the nucleus overcomes resistance, as judged from both in vitro and in vivo studies. The present work highlights the benefits of using a multicomponent small-molecule approach to overcome the complexities associated with drug resistance. It may represent the vanguard of a new paradigm in anticancer drug discovery. Sharma et al. report a cancer-selective multicomponent strategy to overcome drug resistancel. The current strategy centers around a conjugate that triggers a reprogramming of the mitochondrial metabolism. This results in delayed prodrug activation and allows drug efflux mechanisms to be evaded. Compared with various controls, the lead conjugate exhibits cancer-selective activation, restores mitochondrial oxidative phosphorylation, and promotes active doxorubicin (Dox) translocation from mitochondria to the nucleus. It is also significantly more effective at inducing cancer cell apoptosis and tumor growth inhibition in both Dox-sensitive and -resistant tumor models.

Original languageEnglish
Pages (from-to)2370-2383
Number of pages14
JournalChem
Volume4
Issue number10
DOIs
Publication statusPublished - 2018 Oct 11

    Fingerprint

Keywords

  • bioenergetics
  • cancer metabolism
  • carboxylesterase
  • dichloroacetic acid
  • doxorubicin
  • multidrug resistance
  • prodrug
  • SDG3: Good health and well-being
  • targeted therapeutics
  • Warburg effect

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry
  • Environmental Chemistry
  • Chemical Engineering(all)
  • Biochemistry, medical
  • Materials Chemistry

Cite this

Sharma, A., Lee, M. G., Shi, H., Won, M., Arambula, J. F., Sessler, J. L., Lee, J. Y., Chi, S-G., & Kim, J. S. (2018). Overcoming Drug Resistance by Targeting Cancer Bioenergetics with an Activatable Prodrug. Chem, 4(10), 2370-2383. https://doi.org/10.1016/j.chempr.2018.08.002