Mechanism of adriamycin cardiotoxicity: Evidence for oxidative stress

Olson, Richard D.; Boerth, Robert C.; Gerber, John G.; Nies, Alan S.

doi:10.1016/0024-3205(81)90001-1

Cited by 204 publications

(62 citation statements)

References 14 publications

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“…However, in our preparation, caffeine (1 mM), which rapidly depressed contractility, failed to produce significant time-related changes, despite its wellknown ability to release SR Ca2" (Palade, 1987;Pessah et al, 1987) and increase muscle stiffness (Sutko et al, 1986;Schouten, 1990). Similarly, ruthenium red, a negatively inotropic agent that inhibits Ca2" release from SR (Zimanyi & Pessah, 1991 (Boucek et al, 1987b;Olson et al, 1981;Floreani & Carpandeo, 1989;Averbuch et al, 1988;Olson & Mushlin, 1990;Gaudiano & Koch, 1991) (Table 2). On this basis, for doxorubicin and doxorubicinol to make equal contributions to dysfunction associated with doxorubicin treatment, doxorubicinol would need to be 74 fold to 778 fold more potent than doxorubicin to impair subcellular functions (Table 4).…”

Section: Effects Of Doxorubicin and Doxorubicinol On Sr Ca2l Releasementioning

confidence: 73%

Time‐related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function

Mushlin¹,

Cusack²,

Boucek³

et al. 1993

British J Pharmacology

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1 The present study evaluated the time-dependency of acute anthracycline cardiotoxicity by varying the duration of exposure -of rabbit isolated atria to doxorubicin and determing changes (1) in contraction and relaxation and (2) in atrial concentrations of doxorubicin and its C-13 hydroxy metabolite, doxorubicinol.2 Following addition of doxorubicin (175 gM) to atria, contractility (dF/dt), muscle stiffness (resting force, RF) and relaxation (90% relaxation time, 90% RT) were monitored for a 3.5 h period. 3 Doxorubicin (175 iLM) progressively diminished mechanical function (decreased dF/dt, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 gM), however, failed to produce time-related cardiac dysfunction; it depressed contractile function and increased muscle stiffness during the first 30 min without causing additional cardiac dysfunction during the remaining 3 h of observation. Doxorubicinol had no effect on 90% RT. 4 During treatment with doxorubicin, atria contained considerably more doxorubicin than doxorubicinol (ratio of doxorubicin to doxorubicinol ranged from 778 to 74 at 0.5 and 3 h, respectively). Elevations of doxorubicin and doxorubicinol in atria paralleled the degree of dysfunction of both contraction and relaxation; increases in muscle stiffness, however, were more closely associated with increases of doxorubicinol than doxorubicin. 5 To probe the relation between cardiac doxorubicinol and myocardial dysfunction further, without confounding effects of cardiac doxorubicin, concentration-response experiments with doxorubicinol (0.9-7.21EM) were conducted. 6 Plots of doxorubicinol concentrations in atria vs contractility indicated that the cardiac concentration of doxorubicinol, at which contractility is reduced by 50%, is five fold lower in doxorubicin-treated than in doxorubicinol-treated preparations. Thus, doxorubicin and doxorubicinol appear to interact to depress contractile function. 7 Cardiac concentrations of both doxorubicin and doxorubicinol, as observed in these studies, were found to stimulate markedly Ca2" release from isolated SR vesicles, but 3 gM doxorubicinol promoted a 15 fold greater release rate than 3 lM doxorubicin.8 Our observations coupled with the previously reported finding that doxorubicinol inhibits Ca2" loading of SR, suggests that doxorubicinol accumulation in heart contributes to the time-dependent component of doxorubicin cardiotoxicity, through a mechanism that could involve perturbations of Ca2" homeostasis.

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Section: Effects Of Doxorubicin and Doxorubicinol On Sr Ca2l Releasementioning

confidence: 73%

Time‐related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function

Mushlin¹,

Cusack²,

Boucek³

et al. 1993

British J Pharmacology

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“…ing in lipid peroxidation and consequently causing doxorubicin-caused cardiomyopathy (Olson et al, 1988). Antioxidants such as N-acetylcysteine (Powell and McCay, 1988), vitamin E, superoxide dismutase (Hida et al, 1995), and catalase (Myers et al, 1977) decreased the severity of doxorubicin-induced oxidative damage.…”

Section: Takano Et Almentioning

confidence: 99%

Cytoprotection by Metallothionein Against Gastroduodenal Mucosal Injury Caused by Ethanol in Mice

Takano

Satoh

Shimada

et al. 2000

Laboratory Investigation

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SUMMARY:Metallothionein (MT) is a small, cysteine-rich protein that can act as a free radical scavenger at least in vitro. To test the hypothesis that MT participates in gastroduodenal cytoprotection, we studied sensitivity to gastroduodenal mucosal injury caused by ethanol in MT-null mice that have null mutations in MT-I and MT-II genes. MT-null mice and wild-type mice were orally treated with ethanol (60% or 99.5%, 0.2 ml/mouse). The macroscopic gastric lesion indices were significantly higher in MT-null mice than in wild-type mice 90 minutes after ethanol treatment. Histopathological examination in ethanol-treated MT-null mice showed vacuolar degeneration, necrosis of the epithelial cells, and hemorrhage throughout the tunica mucosa. Moreover, the duodenum also showed morphologic changes, including marked degeneration and coagulative necrosis of the entire villi, desquamation of the degenerated epithelial cells, and hemorrhage. In contrast, histopathologic changes were less prominent in the wild-type mice treated with ethanol. MT was not detected either in the stomach or duodenum of MT-null mice, whereas gastric and duodenal zinc contents were not significantly different between MT-null mice and wild-type mice. These results provide direct evidence that intrinsic MT plays a cytoprotective role in gastroduodenal mucosal injury caused by ethanol. (Lab Invest 2000, 80:371-377).

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“…This explains the pathological picture of anthracycline cardioctoxicity characterized by disruption of heart mitochondrial and sarcoplasminc reticulum membranes [42] by drug induced free radical formation in specific myocardial compartments [41]. The free radical hypothesis has been supported by the finding that free radical scavengers attenuate anthracycline-induced myocardial morphofuncianal alternations [43]. Several studies have revealed that polyphenolic antioxidant derived from grape seed extract shows significant pharmacological therapeutic and chemo-protective properties [19].…”

Section: Discussionmentioning

confidence: 98%

The Protective Effect of Grape Seed Extract on Cardiotoxicity Induced by Doxorubicin Drug in Male Rats

Al-Sowayan¹,

Mahmoud²

2014

ABB

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Objective: This work was designed to determine the productive effect of grape seed proanthocynadine extract (GSPE) and Vitamin E against Doxorubicin (DOX) induced myocardial toxicity in 50 male. Wister rates were divided in five groups. The 1 st group was untreated and served as a control. The 2 nd group was treated with DOX only, the 3 rd group was pretreated with GSPE, the 4 th group was pretreated with Vitamin E, and the 5 th group was pretreated with GSPE and Vitamin E. DOX was administered by single i.p (Intraperitonial) injection of 15 mg/kg/body weight to induce cardio toxicity and Vitamin E was administered at a dose of 400 IU/kg/bodyweight/day, p.o (per oral) for 10 days prior to DOX administration [1]. GSPE was given at a dose of 150 mg/kg/bodyweight/ day, p.o (per oral) for 10 days before treatment with DOX. After 2 weeks experimental period, blood samples and heart tissues were taken from all groups. The general observations, mortality, histopathology, biomarker enzymes like Lactate Dehydrogenase (LDH), Creatine Phosphokinase (CPK), Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Antioxidants such as Glutathione (GSH), Superoxide dismutase (SOD), Catalase (CAT) and Malondialdehyde (MDA) were monitored after 2 weeks of the last dose. Results: Administration of DOX caused cardiomyopathy associated with an antioxidant deficiency. Pretreatment with GSPE and Vitamin E significantly (P < 0.01) protected the myocardium from the toxic effects of DOX by reducing the elevated level of biomarkers and diagnostic enzymes like LDH, CPK, AST, and ALT to normal levels. GSPE and Vitamin E increased the GSH, SOD and CAT levels and decreased the MDA levels in cardiac tissue. Conclusion: These results suggest a cardioprotective effect of GSPE and Vitamin E due to its antioxidant properties.

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Mechanism of adriamycin cardiotoxicity: Evidence for oxidative stress

Cited by 204 publications

References 14 publications

Time‐related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function

Time‐related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function

Cytoprotection by Metallothionein Against Gastroduodenal Mucosal Injury Caused by Ethanol in Mice

The Protective Effect of Grape Seed Extract on Cardiotoxicity Induced by Doxorubicin Drug in Male Rats

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