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Review
. 2023 Jul-Dec;27(10):939-952.
doi: 10.1080/14728222.2023.2261631. Epub 2023 Oct 30.

OXPHOS-targeting drugs in oncology: new perspectives

Balaraman Kalyanaraman  1 , Gang Cheng  1 , Micael Hardy  2 , Ming You  3
Affiliations
Review

OXPHOS-targeting drugs in oncology: new perspectives

Balaraman Kalyanaraman et al. Expert Opin Ther Targets. 2023 Jul-Dec.

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.

Keywords: Mitochondrial targets; mitochondrial therapeutics; tumor cells; tumor metastasis; tumor xenografts.

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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Conflict of interest statement

Declaration of Interest:

Balaraman Kalyanaraman is an inventor of US Patent No. 9,956,233, “Neuroprotection by mitochondria-targeted metformin.”

Balaraman Kalyanaraman and Micael Hardy are inventors of US Patent No. 11,274,114, “Modified mito-metformin compounds and methods of synthesis and use thereof”; US Patent No. 10,836,782, “Mito-honokiol compounds and methods of synthesis and use thereof”; and US Patent No. 11,352,382, “Mito-lonidamine, compositions and methods of use.”

Balaraman Kalyanaraman, Gang Cheng, and Micael Hardy are inventors of US Patent No. 11,083,739 and US Patent No. 11,612,610, both titled “Mito-magnolol compounds and methods of synthesis and use thereof,” and WO2021081500A1, “Mitochondria-targeted atovaquone: a more potent and more effective antitumor, antimicrobial, and antimalarial drug,” which is under consideration by the US Patent and Trademark Office.

Figures

Figure 1.
Figure 1.. Chemical Structures of MTDs.
Figure 2.
Figure 2.. Selective uptake of TPP+-based MTDs into tumor mitochondria.
Reprinted (adapted) with permission from Zielonka J, Joseph J, Sikora A, Hardy M, Ouari O, Vasquez-Vivar J, Cheng G, Lopez M, Kalyanaraman B. Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. Chemical Reviews. 2017;117(15):10043–10120. Copyright 2017 American Chemical Society.
Figure 3.
Figure 3.. Comparisons of MTDs and the corresponding parent compounds on cell proliferation inhibitions in human pancreatic cancer (MiaPaCa-2) cells.
The effects of MTDs and their parental compounds on the proliferation of MiaPaCa-2 cells were monitored in the IncuCyte Live-Cell Analysis system. The IC50 values were determined at the point at which control cells reached ~90% confluence. Relative cell confluence (control is taken as 100%) is plotted against concentration. Dashed lines represent the fitting curves used to determine the IC50 values as indicated. The folder of differences as indicated were calculated by the potency difference of the IC50 values between each mitochondria-targeted drug and its parental compound. The IC50 values of Mito-Met and metformin were published previously in Cancer Research (Cheng G et al., Cancer Res, 2016). The IC50 values of Mito-ATO and ATO were published in Scientific Reports (Cheng G et al., Scientific Reports, 2020; Cheng G et al., Scientific Reports, 2022). This figure is re-used under CC BY 4.0 from Cheng G, Hardy M, Kalyanaraman B. Antiproliferative Effects of Mitochondria-Targeted N-acetylcysteine and Analogs in Cancer Cells. Scientific Reports. 2023;13:7254.
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