Abstract
Doxorubicin (DOX) is a highly effective treatment for several forms of cancer. However, clinical experience shows that DOX induces a cumulative and dose-dependent cardiomyopathy that has been ascribed to redox-cycling of the drug on the mitochondrial respiratory chain generating free radicals and oxidative stress in the process. Mitochondrial dysfunction including induction of the mitochondrial permeability transition (MPT) and inhibition of mitochondrial respiration have been implicated as major determinants in the pathogenesis of DOX cardiotoxicity. The present work was aimed at investigating whether the inhibition of mitochondrial respiration occurs secondarily to MPT induction in heart mitochondria isolated from DOX-treated rats and whether one or both consequences of DOX treatment are related with oxidation of protein thiol residues. DOX-induced oxidative stress was associated with the accumulation of products of lipid peroxidation and the depletion of α-tocopherol in cardiac mitochondrial membranes. No changes in mitochondrial coenzyme Q9 and Q10 concentrations were detected in hearts of DOX-treated rats. Cardiac mitochondria from DOX-treated rats were more susceptible to diamide-dependent induction of the MPT. Although DOX treatment did not affect state 4 respiration, state 3 respiration was decreased in heart mitochondria isolated from DOX-treated rats, which was reversed in part by adding either cyclosporin A or dithiothreitol, but not Trolox. The results suggest that in DOX-treated rats, (i) induction of the MPT is at least in part responsible for decreased mitochondrial respiration, (ii) heart mitochondria are more susceptible to diamide induced-MPT, (iii) thiol-dependent alteration of mitochondrial respiration is partially reversible ex vivo with dithiothreitol. Collectively, these data are consistent with the thesis that thiol-dependent alteration of MPT and respiration is an important factor in DOX-induced mitochondrial dysfunction.
Original language | English (US) |
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Pages (from-to) | 194-199 |
Number of pages | 6 |
Journal | Biochemistry (Moscow) |
Volume | 71 |
Issue number | 2 |
DOIs | |
State | Published - Jan 2006 |
Bibliographical note
Funding Information:This work was supported by the NIH grant HL 58016. Paulo J. Oliveira is supported by a grant from the Portuguese Foundation for Science and Technology (SFRH/BPD/8359/2002).
Keywords
- Doxorubicin
- Heart
- Mitochondria
- Oxidative stress