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

doi:10.1016/j.isci.2022.104340

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

iScience. 2022 Apr 30;25(5):104340. doi: 10.1016/j.isci.2022.104340. eCollection 2022 May 20.

Authors

Chibuzor Olelewe¹, Jong Hyun Kim¹, Samuel Ofori¹, Randall T Mertens¹, Sailajah Gukathasan¹, Samuel G Awuah^{1

2

3}

Affiliations

¹ Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
² Center for Pharmaceutical Research and Innovation, College of Pharmacy and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
³ Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.

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.

Keywords: Biochemistry; Biological sciences; Cancer; Small molecule.

Abstract

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