Doxorubicin Cytotoxicity in Differentiated H9c2 Cardiomyocytes: Evidence for Acute Mitochondrial Superoxide Generation
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Doxorubicin Cytotoxicity in Differentiated H9c2 Cardiomyocytes: Evidence for Acute Mitochondrial Superoxide Generation Muath Helal1 · Jane Alcorn1 · Brian Bandy1 Received: 24 May 2020 / Accepted: 31 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Although a mitochondrial redox-cycling superoxide-generating mechanism for the cardiotoxicity of doxorubicin was suggested from experiments with isolated mitochondria, its occurrence and contribution to cytotoxicity in intact cardiomyocytes is not fully established. Therefore, we determined the immediate and delayed effects of doxorubicin on the generation of reactive oxygen species (ROS) and cytotoxicity in differentiated H9c2 cardiomyocytes. Although relatively short incubations (3 or 6 h) with 1 or 5 µM doxorubicin did not acutely decrease cell survival, exposure to 5 µM doxorubicin for 3 h was sufficient to cause a significant delayed decrease in cell survival after an additional 24 h without doxorubicin. Mitochondrial superoxide generation was observed to increase within 30 min of incubation with 5 µM doxorubicin. Increased intracellular ROS generation, decreased mitochondrial metabolic activity, and decreased mitochondrial membrane potential (MMP) were observed after more extended periods (6–12 h). Overall, these observations support that the toxicity of doxorubicin to differentiated cardiomyocytes involves acute mitochondrial superoxide generation with subsequent intracellular ROS generation, mitochondrial dysfunction, and cell death. Keywords Doxorubicin · Cardiomyocyte cytotoxicity · Mitochondrial superoxide · Intracellular ROS · Mitochondrial dysfunction · Cell death
Introduction Doxorubicin is a chemotherapeutic agent widely used for different cancer types [1]. Doxorubicin exerts anti-cancer biological activity by mechanisms involving intercalation into DNA and impairing topoisomerase-II [1–3]. Despite its wide implementation in various cancer therapy regimens, its dosage is limited by cardiotoxicity and other organ toxicity [4–7]. While a widely suggested cause for cardiotoxicity is the over production of reactive oxygen species (ROS), primarily in the heart mitochondria [8–10], other mechanisms have previously and recently been proposed [11–14]. Handling Editor: Matthew Campen. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12012-020-09606-1) contains supplementary material, which is available to authorized users. * Brian Bandy [email protected] 1
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
The production of ROS in heart cells, which are rich in mitochondria, is thought to be mediated largely by the redox cycling activity of doxorubicin in mitochondrial complex I [8, 9]. This mechanism was originally observed in experiments with purified NADH dehydrogenase and isolated heart submitochondrial particles [15, 16], but whether it mediates the cytotoxicity of doxorubicin in intact cardiomyocytes has not been fully co
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