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Article Dans Une Revue Expert Opinion on Therapeutic Targets Année : 2023

OXPHOS-targeting drugs in oncology: new perspectives

Résumé

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. Plain Language Summary Mitochondria, which are the cell’s powerhouse of energy, are functional in cancer cells. Inhibition of cancer cell respiration is associated with inhibition of cancer cell proliferation. Therefore, mitochondria have become a promising target for developing antitumor drugs to treat cancer. Several classes of drug molecules selectively target cancer cell mitochondria and inhibit mitochondrial respiration or oxidative phosphorylation (OXPHOS). A new class of OXPHOS-targeting drugs is emerging as a potential cancer therapeutic. One of the OXPHOS inhibitor drugs, IACS-010759, developed by investigators at MD Anderson Cancer Center, was tested in patients with acute myeloid leukemia. Patients who were administered the drug developed peripheral neuropathy and other complications (lactic acidosis), resulting in dose reduction. At lower doses, this drug was not effective. Subsequently, the clinical trial was terminated. The investigators then showed the same type of neurotoxicity using a mouse model. These findings were recently published. Thus, there is an urgent need to develop new OXPHOS inhibitors that do not have neurotoxicity in mice or humans. In this opinion article, we make a case that there are other triphenylphosphonium cation (TPP+)-based mitochondrial OXPHOS inhibitors (inhibiting both complex I and complex III) that are structural modifications of naturally occurring molecules or US FDA-approved drugs. These mitochondria-targeted drugs (MTDs) are as potent as IACS-010759 in cells and in preclinical models. Several TPP+-based MTDs have been tested in mice and did not exert neurotoxicity. TPP+-containing MTDs such as mitochondria-targeted coenzyme Q10 (MitoQ) have 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 [ATO] or papaverine) are in clinical trials alone or in combination with other standard-of-care treatments (e.g., radiation therapy). We recommend that TPP+-based drugs that have been tested in preclinical models or in humans should undergo clinical trials in patients with cancer.

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Chimie
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hal-04506372 , version 1 (15-03-2024)

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Paternité - Pas d'utilisation commerciale - Pas de modification

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Balaraman Kalyanaraman, Gang Cheng, Micael Hardy, Ming You. OXPHOS-targeting drugs in oncology: new perspectives. Expert Opinion on Therapeutic Targets, 2023, 27 (10), pp.939-952. ⟨10.1080/14728222.2023.2261631⟩. ⟨hal-04506372⟩
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