Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice.

Kristell Le Gal,Clotilde Wiel,Mohamed X Ibrahim,Volkan I Sayin,Martin O Bergo,Marcus Henricsson

doi:10.3390/antiox10020163

Kristell Le Gal, Clotilde Wiel + Show 4 more

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https://doi.org/10.3390/antiox10020163

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Journal: Antioxidants	Publication Date: Jan 22, 2021
Citations: 15	License type: CC BY 4.0

Affiliation: University of Gothenburg, Karolinska Institutet

Abstract

Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, we administered the mitochondria-targeted antioxidants MitoQ and MitoTEMPO to mice with BRAF-induced malignant melanoma and KRAS-induced lung cancer, and found that these compounds had no impact on the number of primary tumors and metastases; and did not influence mitochondrial and nuclear DNA damage levels. Moreover, MitoQ and MitoTEMPO did not influence proliferation of human melanoma and lung cancer cell lines. MitoQ and its control substance dTPP, but not MitoTEMPO, increased glycolytic rates and reduced respiration in melanoma cells; whereas only dTPP produced this effect in lung cancer cells. Our results do not support the use of mitochondria-targeted antioxidants for anti-cancer monotherapy, at least not in malignant melanoma and lung cancer.

Highlights

Reactive oxygen species (ROS) damage cellular structures and cause oxidative stress, but they function as signaling molecules that regulate biological and pathological processes [1]
To define effects of mitochondria-targeted antioxidants on the progression of malignant melanoma, we first used MitoQ, a MitoQuinone conjugated with the lipophilic triphenylphosphonium (TPP) cation that stimulates its accumulation in the inner mitochondrial membrane [20]
We found that MitoQ and MitoTEMPO administration had no impact on the number of primary tumors and lymph metastases in mice with BRAF-induced malignant melanoma and no impact on tumor burden in mice with KRAS-induced lung cancer

Summary

Introduction

Reactive oxygen species (ROS) damage cellular structures and cause oxidative stress, but they function as signaling molecules that regulate biological and pathological processes [1]. Mitochondria produce a substantial portion of cellular ROS, in particular superoxide (O2 ), as a byproduct of oxidative phosphorylation in complexes I, II, and III of the electron transport chain (ETC) [2]. O2 is rapidly converted to hydrogen peroxide (H2 O2 ) by the enzymatic activity of superoxide dismutases (SODs) located in the mitochondrial matrix [3]. The mitochondria-associated H2 O2 can in turn stimulate intracellular signaling pathways by reversibly oxidizing cysteine residues in key proteins [4,5]. Cancer cells produce high levels of mitochondria-associated H2 O2 that can promote growth and proliferation [6,7]. Oxidation-induced inactivation of the tumor suppressor protein PTEN increases PI3K signaling and stimulates cell growth and proliferation [8]. Mitochondrial superoxide production can drive metastasis by activating

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