Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers

Abstract

Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone’s potential as a gynecologic cancer therapeutic.

Recent advances in understanding the metabolic plasticity of ovarian cancer: A systematic review

“…However, there is growing evidence that HGSC and CCC undergo metabolic reprogramming toward OXPHOS that allows them to survive [ 55 , 56 ] (non-CSCs are marked “D” in Figure 3 ). Notably, CCC cell lines (ES-2 and TOV-21-G) were highly metabolically active, with increased expression of glycolysis-related genes [ 39 ].…”

“…[ 55 ] provided an overview of the metabolic function in HGSC, summarized the role of small-molecule inhibitors of OXPHOS, elucidated the mechanism of action of the drugs, and suggested ways to overcome the clinical problem. Furthermore, antidiabetic agents (e.g., metformin and thiazolidinediones) and anti-malaria agents (e.g., atovaquone) have been reported to suppress cancer cell proliferation by inhibiting the mitochondrial electron transport chain [ 55 , 56 ]. In addition, treatment strategies with OXPHOS inhibition to eradicate chemoresistant cancer stem cells have also been studied [ 2 ].…”

Strategies to Reverse Hypoxic Tumor Microenvironment for Enhanced Sonodynamic Therapy

“…Atovaquone (ATO), a hydroxy‐1,4‐naphthoquinone analog of ubiquinone, can selectively target CoQ10‐dependence in complex III (cytochrome bc1 complex) of the OXPHOS to improve tumor oxygenation. [ 84 ] ATO has been successfully utilized in the antitumor modalities to enhance the therapeutic effects in the oxygen‐dependent therapies and has been shown to effectively reverse tumor hypoxia at the clinical doses. [ 85 ] A virus‐like nanocapsule named PHAR, composed mainly of polydopamine (PDA) energy converter, the sonosensitizer “chlorin e6‐C‐15‐ethyl ester” (HB), and the OXPHOS inhibitor ATO, showed photothermal‐augmented SDT in a tumor‐bearing mouse model (Figure 1C).…”

Immunogenic Radiation Therapy for Enhanced Antitumor Immunity via a Core–Shell Nanosensitizer-Mediated Immunosuppressive Tumor Microenvironment Modulation

“…However, a large amount of oxygen is consumed by the abnormal proliferation of solid tumors, leading to serious hypoxia in the TME and severe limitation in oxygen-dependent therapeutics, typically for RT. Current tumor oxygenation strategies include two main approaches: one is to increase oxygen supply by increasing blood supply (e.g., erlotinib and nitric oxide), , carrying oxygen (e.g., fluorocarbon and metal–organic frameworks), , and generating oxygen in situ (e.g., catalase and catalase-like nanozymes); the other is to reduce oxygen consumption by inhibiting cellular respiration (e.g., atovaquone and metformin). , Nonetheless, strategies to increase oxygen supply may be hindered by low vascular remodeling efficiency, oxygen transport capacity, and intrinsic hydrogen peroxide (H 2 O 2 ) content . In contrast, inhibition of oxygen consumption can be more efficient in improving tumor oxygenation and can benefit oxygen-dependent RT.…”