Gold(III)-P-chirogenic complex induces mitochondrial dysfunction in triple-negative breast cancer

Chibuzor Olelewe, Jong Hyun Kim, Samuel Ofori, Randall T. Mertens, Sailajah Gukathasan, Samuel G. Awuah

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Chemical agents that specifically exploit metabolic vulnerabilities of cancer cells will be beneficial but are rare. The role of oxidative phosphorylation (OXPHOS) in promoting and maintaining triple-negative breast cancer (TNBC) growth provides new treatment opportunity. In this work, we describe AuPhos-19, a small-molecule gold(III)-based agent bearing a chiral phosphine ligand that selectively disrupts mitochondrial metabolism in murine and human TNBC cells but not normal epithelial cells. AuPhos-19 induces potent cytotoxic effect with half maximal inhibitory concentration (IC50) in the nanomolar range (220–650 nM) across different TNBC cell lines. The lipophilic cationic character of AuPhos-19 facilitates interaction with mitochondrial OXPHOS. AuPhos-19 inhibits mitochondria respiration and induces significant AMPK activation. Depolarization of the mitochondria membrane, mitochondria ROS accumulation, and mitochondria DNA depletion provided further indication that AuPhos-19 perturbs mitochondria function. AuPhos-19 inhibits tumor growth in tumor-bearing mice. This study highlights the development of gold-based compounds targeting mitochondrial pathways for efficacious cancer treatment.

Original languageEnglish
Article number104340
JournaliScience
Volume25
Issue number5
DOIs
StatePublished - May 20 2022

Bibliographical note

Publisher Copyright:
© 2022

Keywords

  • Biochemistry
  • Biological sciences
  • Cancer
  • Small molecule

ASJC Scopus subject areas

  • General

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