Abstract
BackgroundWhile doxorubicin (DOX) is widely used in cancer chemotherapy, long-term severe cardiotoxicity limits its use. This is the first report of the chemoprotective efficacy of a relatively new thiol antioxidant, N-acetylcysteine amide (NACA), on DOX-induced cell death in cardiomyocytes. We hypothesized that NACA would protect H9c2 cardiomyocytes from DOX-induced toxicity by reducing oxidative stress. Accordingly, we determined the ability of NACA to mitigate the cytotoxicity of DOX in H9c2 cells and correlated these effects with the production of indicators of oxidative stress.ResultsDOX at 5 μM induced cardiotoxicity while 1) increasing the generation of reactive oxygen species (ROS), 2) decreasing levels and activities of antioxidants and antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase) and 3) increasing lipid peroxidation. NACA at 750 μM substantially reduced the levels of ROS and lipid peroxidation, as well as increased both GSH level and GSH/GSSG ratio. However, treating H9c2 cells with NACA did little to protect H9c2 cells from DOX-induced cell death.ConclusionAlthough NACA effectively reduced oxidative stress in DOX-treated H9c2 cells, it had minimal effects on DOX-induced cell death. NACA prevented oxidative stress by elevation of GSH and CYS, reduction of ROS and lipid peroxidation, and restoration of antioxidant enzyme activities. Further studies to identify oxidative stress-independent pathways that lead to DOX-induced cell death in H9c2 are warranted.
Highlights
While doxorubicin (DOX) is widely used in cancer chemotherapy, long-term severe cardiotoxicity limits its use
The in vitro metabolism of DOX by cardiac and liver microsomal membranes includes enzymes such as cytosolic xanthine oxidase, microsomal nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductase, which is present in all tissues, and mitochondrial cytosolic NADPH dehydrogenase, which is uniquely present in cardiac cells [6,7]
Cytotoxicity of doxorubicin (DOX) and N-acetylcysteine amide (NACA) on H9c2 cells To determine a sublethal concentration of NACA for the study on its ability to protect H9c2 cells from DOXinduced toxicity, we first exposed cells with NACA at 0.25 mM, 0.50 mM, 0.75 mM, 1 mM, 2 mM, 5 mM, 10 mM, and 20 mM for 24 h
Summary
While doxorubicin (DOX) is widely used in cancer chemotherapy, long-term severe cardiotoxicity limits its use. This is the first report of the chemoprotective efficacy of a relatively new thiol antioxidant, N-acetylcysteine amide (NACA), on DOX-induced cell death in cardiomyocytes. DOX is bio-reduced to a semiquinone free radical that rapidly undergoes 1) further reduction to a hydroquinone, 2) formation of covalent adducts with DNA or proteins, or 3) transfer of the unpaired electron to an electron acceptor [8]. Cause peroxidation of unsaturated membrane lipids and induce irreversible tissue damage by inactivating key proteins and enzymes present in the cardiac sarcoplasmic reticulum and in the mitochondrial respiratory chain [9,10,11] Superoxide, H2O2, and HO. cause peroxidation of unsaturated membrane lipids and induce irreversible tissue damage by inactivating key proteins and enzymes present in the cardiac sarcoplasmic reticulum and in the mitochondrial respiratory chain [9,10,11]
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