OXPHOS-targeting drugs in oncology: new perspectives

Balaraman Kalyanaraman, Gang Cheng, Micael Hardy, Ming You

Research output: Contribution to journalReview articlepeer-review

9 Scopus citations

Abstract

Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy. Areas covered: Triphenylphosphonium cation (TPP+)-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP+-based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies. Expert opinion: TPP+-based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP+-based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP+-based OXPHOS-inhibiting drugs in cancer prevention and treatment.

Original languageEnglish (US)
Pages (from-to)939-952
Number of pages14
JournalExpert Opinion on Therapeutic Targets
Volume27
Issue number10
DOIs
StatePublished - 2023

Keywords

  • Mitochondrial targets
  • mitochondrial therapeutics
  • tumor cells
  • tumor metastasis
  • tumor xenografts

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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