The protective effect of glutathione administration on adriamycin-induced acute cardiac toxicity in rats

Mohamed, H. E.; Elswefy, Sahar E; Hagar, Hanan

doi:10.1006/phrs.1999.0630

Cited by 58 publications

(39 citation statements)

References 24 publications

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“…The molecular basis of AN-7 protection against Dox-induced cardiotoxicity could be explained by a number of different molecular mechanisms such as the protection of mitochondrial functions or reduced degradation of Dox to its toxic metabolite doxorubicinol (Mohamed et al, 2000;Minotti et al, 2001). Additional known damaging effects of Dox are the generation of ROS as well as the inhibition of the ROS detoxifying enzyme, glutathione peroxidase (Li et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…The molecular basis of Dox-induced cardiotoxicity is attributed to several different molecular events: generation of reactive oxygen species (ROS), impaired calcium homeostasis and mitochondrial functions, reduced expression of energy-generating enzymes and degradation of Dox to its toxic metabolite doxorubicinol (Mohamed et al, 2000;Minotti et al, 2001). The vulnerability of the heart to ROS is further intensified by Dox inhibition of ROS neutralising enzymes (Li et al, 2000).…”

mentioning

confidence: 99%

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Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

et al. 2007

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Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (DCm) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

et al. 2007

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“…However, the doxorubicin-treated hearts in our study became markedly sensitive to the deleterious effect of hydrogen peroxide. A possible explanation for this finding is that the prolonged production of reactive oxidants and free radicals in the doxorubicin-treated heart diminishes the oxygen free radical scavenging capacity, i.e., superoxide dismutase (SOD), glutathione peroxidase (GSHpx) and catalase activity, and hence suppresses endogenous antioxidant levels (such as glutathione) [26,27]. Therefore, it is conceivable that in the heart, the vital antioxidant system is depressed and, therefore, the hearts became more sensitive to an acute oxidative insult.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure

Szenczi

Kemecsei

Holthuijsen

et al. 2005

Biochemical Pharmacology

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Reactive oxygen and nitrogen species are overproduced in the cardiovascular system in response to the exposure to doxorubicin, a cardiotoxic anticancer compound. Oxidant-induced cell injury involves the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and pharmacological inhibition of PARP has recently been shown to improve myocardial contractility in doxorubicin-induced heart failure models. The current investigation, by utilizing an isolated perfused heart system capable of beat-to-beat intracellular calcium recording, addressed the following questions: (1) is intracellular calcium handling altered in hearts of rats after 6-week doxorubicin treatment, under baseline conditions, and in response to oxidative stress induced by hydrogen peroxide exposure in vitro; and (2) does pharmacological inhibition of PARP with the phenanthridinone-based PARP inhibitor PJ34 affect the changes in myocardial mechanical performance and calcium handling in doxorubicin-treated hearts under normal conditions and in response to oxidative stress. The results showed a marked elevation in intracellular calcium in the doxorubicin-treated hearts which was normalized by pharmacological inhibition of PARP. PARP inhibition also prevented the myocardial contractile disturbances and calcium overload that developed in response to hydrogen peroxide in the doxorubicin-treated hearts. We conclude that PARP activation contributes to the development of the disturbances in cellular calcium handling that develop in the myocardium in response to prolonged doxorubicin exposure.

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“…Thus nontrained animals were distributed into nontrained ϩ placebo (NT ϩ P, n ϭ 10) and nontrained ϩ DOX (NT ϩ DOX, n ϭ 10) groups and trained animals into trained ϩ placebo (T ϩ P, n ϭ 10) and trained ϩ DOX (T ϩ DOX, n ϭ 10) groups. The placebo groups were injected with a saline solution (0.9% NaCl ip) and the DOX groups with a single dose of DOX (20 mg/kg ip) in solution according to previous studies (9,38). Both treatments were carried out 24 h before the animals were killed.…”

Section: Methodsmentioning

confidence: 99%

Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis

Ascensão¹,

Magalhães²,

Soares³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

129

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The protective effect of glutathione administration on adriamycin-induced acute cardiac toxicity in rats

Cited by 58 publications

References 24 publications

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure

Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis

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