Protective Effect of Captopril against Doxorubicin-Induced Oxidative Stress in Isolated Rat Liver Mitochondria (original) (raw)
Related papers
Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity
ACS Chemical Biology, 2015
The highly effective anticancer agent doxorubicin (Dox), is a frontline drug used to treat a number of cancers including leukemias, ovarian, prostate, breast, and lung cancer. While Dox has a high level of activity against cancer cells, treatment is often complicated by doselimiting cardiotoxicity. For many years, this debilitating side effect is thought to originate from the drug's direct activity in the mitochondria of cardiac cells, while recent studies have shown that these are primarily downstream effect from nuclear damage. Our lab has developed a mitochondrially-targeted derivative of Dox that enables the selective study of toxicity generated by the presence of Dox in the mitochondria of H9c2 rat cardiomyocytes. We demonstrate that mitochondria-targeted doxorubicin (mtDox) lacks any direct nuclear effects, which allows the cardiomyocytes to undergo mitochondrial biogenesis. This recovery response compensates for the mitotoxic effects of Dox and prevents cell death in cardiomyocytes. In accordance with these findings, cardiac toxicity was only observed in Dox but not mtDox treated mice. This study provides valuable insight into the development of methods to effectively limit the debilitating cardiotoxic effects of Dox, and potentially of other chemotherapeutics that exert effects on multiple subcellular organelles..
2002
There have been very few investigations as to whether mitochondrialmediated apoptosis in vivo is the underlying mechanism of doxorubicin cardiotoxicity. Moreover, no investigations have been conducted to determine whether there are adaptive responses after doxorubicin treatment. We administered a single dose of doxorubicin (20 mg/kg) to male rats and isolated intact mitochondria from their hearts 4 days later. Apoptosis, as determined by the amount of cytosolic mononucleosomal and oligonucleosomal DNA fragments (180 bp or multiples), was significantly increased after doxorubicin treatment. In contrast, Troponin-T, a cardiac-specific marker for necrotic damage, was unaltered 4 days after doxorubicin treatment. Cytosolic cytochrome c increased 2-fold in the doxorubicintreated rats and was significantly correlated (r ؍ 0.88; P < 0.01) with the increase in caspase-3 activity observed. Moreover, the level of bleomyocindetectable iron in serum was significantly increased and may have contributed to the increase in oxidative stress, which was indicated by an increase in cytosolic 8-iso prostaglandin F 2␣ . Cytosolic copper zinc superoxide dismutase activity also increased significantly further supporting the notion that doxorubicin increases superoxide radical production. In addition to adaptations to antioxidant defenses, other adaptive mechanisms occurred in the mitochondria such as an increase in the respiratory P/O ratio and an increase in the Bcl-2:Bax ratio. These findings demonstrate that doxorubicin induces oxidative stress and mitochondrial-mediated apoptosis, as well as adaptive responses by the mitochondria to protect cardiac myocytes in vivo.
Cardiovascular Toxicology, 2020
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.
PLoS ONE, 2012
Although doxorubicin (DOX) is a very effective antineoplastic agent, its clinical use is limited by a dose-dependent, persistent and cumulative cardiotoxicity, whose mechanism remains to be elucidated. Previous works in animal models have failed to use a multi-organ approach to demonstrate that DOX-associated toxicity is selective to the cardiac tissue. In this context, the present work aims to investigate in vivo DOX cardiac, hepatic and renal toxicity in the same animal model, with special relevance on alterations of mitochondrial bioenergetics. To this end, male Wistar rats were sub-chronically (7 wks, 2 mg/Kg) or acutely (20 mg/Kg) treated with DOX and sacrificed one week or 24 hours after the last injection, respectively. Alterations of mitochondrial bioenergetics showed treatment-dependent differences between tissues. No alterations were observed for cardiac mitochondria in the acute model but decreased ADP-stimulated respiration was detected in the sub-chronic treatment. In the acute treatment model, ADP-stimulated respiration was increased in liver and decreased in kidney mitochondria. Aconitase activity, a marker of oxidative stress, was decreased in renal mitochondria in the acute and in heart in the sub-chronic model. Interestingly, alterations of cardiac mitochondrial bioenergetics co-existed with an absence of echocardiograph, histopathological or ultra-structural alterations. Besides, no plasma markers of cardiac injury were found in any of the time points studied. The results confirm that alterations of mitochondrial function, which are more evident in the heart, are an early marker of DOX-induced toxicity, existing even in the absence of cardiac functional alterations.
Mitochondrial dysfunction is an early indicator of doxorubicin-induced apoptosis
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2002
Generation of reactive oxygen species and mitochondrial dysfunction has been implicated in doxorubicin-induced cardiotoxicity. This study examined pro-apoptotic mitochondrial cell death signals in an H9C2 myocyte rat cell line and in isolated rat heart mitochondria exposed to doxorubicin. Mitochondrial and cellular viability were assessed using an MTT viability assay (formazan product formed by functional mitochondrial dehydrogenases) and calcein AM dye (fluoresces upon cleavage by cytosolic esterases). Mitochondrial dysfunction followed by cell death was observed using nM concentrations of doxorubicin. Significant doxorubicin-induced cell death was not apparent until after 6 h following doxorubicin exposure using the calcein AM assay. The involvement of apoptosis is evidenced by an increase in TUNEL (terminal (TdT)-mediated dUTP-biotin nick end labeling)-positive nuclei following doxorubicin treatment. Furthermore, doxorubicin administered to isolated mitochondria induced a rapid increase in superoxide production, which persisted for at least 1 h and was followed by increased cytochrome c efflux. In addition, caspase-3 activity was increased with doxorubicin administration in the H9C2 myocyte cell line. An oxidant-mediated threshold of mitochondrial death may be required for doxorubicin-induced apoptosis.
Aspects related to oxidative stress-mediated toxicity of doxorubicin during chemotherapy treatment
Objective: This study aimed to describe the main toxic effects mediated by oxidative stress associated with treatment with doxorubicin in scientific research articles available in the literature. Material and Methods: This study employed a descriptive review methodology applied to the literature. For the theoretical scientific background, we used the electronic PubMed search engines. Conclusion: The toxicity of chemotherapy treatment with doxorubicin causes damage in various organs of patients who are in uninterrupted treatment with this antineoplastic agent. Anthracycline-induced cardiotoxicity has been investigated to a great degree and is especially indicated as the principal side effect. Therefore, care needs to be given to other damage caused by this medication as important as myocardial toxicity, such as renal, pulmonary and liver toxicity, among others. There is a need for further studies to prevent or even encounter a way to control the damage caused by these toxicities in various tissues.
Molecular Pharmacology, 2019
Doxorubicin (DOX) is one of the most effective anticancer drugs to treat various forms of cancers; however, its therapeutic utility is severely limited by its associated cardiotoxicity. Despite the enormous amount of research conducted in this area, the exact molecular mechanisms underlying DOX toxic effects on the heart are still an area that warrants further investigations. In this study, we reviewed literature to gather the best-known molecular pathways related to DOX-induced cardiotoxicity (DIC). They include mechanisms dependent on mitochondrial dysfunction such as DOX influence on the mitochondrial electron transport chain, redox cycling, oxidative stress, calcium dysregulation, and apoptosis pathways. Furthermore, we discuss the existing strategies to prevent and/or alleviate DIC along with various techniques available for therapeutic drug monitoring (TDM) in cancer patients treated with DOX. Finally, we propose a stepwise flowchart for TDM of DOX and present our perspective at curtailing this deleterious side effect of DOX.
Molecular Mechanisms of Cardiotoxicity: A Review on Major Side-effect of Doxorubicin
Indian Journal of Pharmaceutical Sciences
Mobaraki, et al.: Molecular Mechanisms of Doxorubicin-induced Cardiotoxicity Doxorubicin is among the most widely used drugs for the treatment of both adult and child cancers. Doxorubicin is the major cause of chemotherapy-induced cardiotoxicity that is dose limiting for the treatment of cancer. Many studies have explored pathophysiology and mechanisms of doxorubicininduced cardiotoxicity. Cellular and animal experiments proposed that doxorubicin-induced cardiotoxicity mechanism is multifactorial. Oxidative stress has been considered as the primary cause of cardiotoxicity. Although there is no effective treatment for doxorubicin-induced cardiotoxicity currently but many investigations are underway to discover preventive treatments whereas no specific treatment has been approved. Studies have shown that reactive oxygen species and topoisomerase 2b are molecular targets for cardioprotection. Therapeutic imaging methods and cardio-biomarkers may be helpful in the improvement of rapid detection of cardiac damage. In this review, effects of doxorubicin on DNA damage, free radical generation, mitochondrial damage, cell death and other parameters have been studied.