New Perspectives on OXPHOS-Targeting Drugs for Cancer
Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. In their article, "OXPHOS-targeting drugs in oncology: new perspectives,” published in Expert Opinion in Therapeutic Targets, co-authors Balaraman Kalyanaraman, PhD, MCW professor of biophysics and the Harry R. & Angeline E. Quadracci Professor in Parkinson’s Research; Gang Cheng, PhD, MCW assistant professor of biophysics; Micael Hardy, PhD, of Aix-Marseille Université, France; and Ming You, MD, PhD, of Houston Methodist Research Institute, discuss the urgency of developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index as an alternative strategy to treat cancer.
In this review article, the authors discuss that other triphenylphosphonium-based mitochondrial OXPHOS inhibitors (inhibiting both complex I and complex III) that are structural modifications of naturally occurring molecules or US FDA-approved drugs could be as potent as IACS-010759 in cells and in preclinical models. For example, mitochondria-targeted coenzyme Q10 (MitoQ) has been tested in patients with Parkinson’s disease with no evidence of peripheral neuropathy or other toxicity (e.g., lactic acidosis).
Other US FDA-approved drugs (metformin and atovaquone or papaverine) are in clinical trials alone or in combination with other standard-of-care treatments (e.g., radiation therapy). The authors recommend that triphenylphosphonium-based drugs that have been tested in preclinical models or in humans should undergo clinical trials in patients with cancer.