Edaravone, a potent free radical scavenger, prevents anthracycline-induced myocardial cell death.
ABSTRACT It was investigated whether edaravone, a potent free radical scavenger, would protect against anthracycline-induced cardiotoxicity and prevent cardiac function deterioration.
Cultured neonatal rat cardiomyocytes were stimulated by daunorubicin 1 mumol/L either with or without edaravone or superoxide dismutase mimetic Mn (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP). Cell viability was estimated by measuring the amount of lactate dehydrogenase (LDH) released into the culture medium. Apoptosis was determined by a caspase-3 activity assay and a histone - DNA complex fragment assay. To investigate whether edaravone interfered with daunorubicin's anti-tumor effect, daunorubicin and edaravone were added to human leukemia K562 cells, and the surviving cells were counted. In addition, edaravone's in vivo effect was evaluated using Sprague - Dawley rats. A total of 15 mg/kg doxorubicin was injected intraperitoneally either with or without simultaneous edaravone injection. Two and 6 weeks after the final injection, left ventricular diastolic diameter and left ventricular fraction shortening were assessed echocardiographically. The LDH assay showed that edaravone significantly inhibited LDH release from cardiac myocytes (p=0.0428). The caspase-3 activity and histone - DNA complex fragment assays demonstrated that edaravone's apoptosis suppression effect was much weaker than that of MnTMPyP. The in vivo study showed that edaravone prevented doxorubicin-induced cardiac deterioration. Finally, edaravone was found to not affect daunorubicin's anticancer effect on K562 cells.
Edaravone protects cardiomyocytes from anthracycline-induced cardiotoxicity via an anti-necrotic rather than an anti-apoptotic effect.
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ABSTRACT: Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid (Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies, involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes. Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum histone deacetylase inhibitors tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination therapies for cancer.Cellular and Molecular Life Sciences CMLS 05/2011; 68(24):4101-14. · 5.62 Impact Factor
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ABSTRACT: The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of malignancies. Previous studies suggest that doxorubicin-associated cardiotoxicity is mediated by reactive oxygen species (ROS)-induced apoptosis. We therefore investigated if baicalein, a natural antioxidant component of Scutellaria baicalensis, could attenuate ROS generation and cell death induced by doxorubicin. Using an established chick cardiomyocyte model, doxorubicin (10 µM) increased cell death in a concentration- and time-dependent manner. ROS generation was increased in a dose-response fashion and associated with loss of mitochondrial membrane potential. Doxorubicin also augmented DNA fragmentation and increased the phosphorylation of ROS-sensitive pro-apoptotic kinase c-Jun N-terminal kinase (JNK). Adjunct treatment of baicalein (25 µM) and doxorubicin for 24 h significantly reduced both ROS generation (587 ± 89 a.u. vs. 932 a.u. ± 121 a.u., P < 0.01) and cell death (30.6 ± 5.1% vs. 46.8 ± 8.3%, P < 0.01). The dissipated mitochondrial potential and increased DNA fragmentation were also ameliorated. Along with the reduction of ROS and apoptosis, baicalein attenuated phosphorylation of JNK induced by doxorubicin (1.7 ± 0.3 vs. 3.0 ± 0.4-fold, P < 0.05). Co-treatment of cardiomyocytes with doxorubicin and JNK inhibitor SP600125 (10 µM; 24 h) reduced JNK phosphorylation and enhanced cell survival, suggesting that the baicalein protection against doxorubicin cardiotoxicity was mediated by JNK activation. Importantly, concurrent baicalein treatment did not interfere with the anti-proliferative effects of doxorubicin in human breast cancer MCF-7 cells. In conclusion, baicalein adjunct treatment confers anti-apoptotic protection against doxorubicin-induced cardiotoxicity without compromising its anti-cancer efficacy.Journal of Cellular Biochemistry 05/2011; 112(10):2873-81. · 3.06 Impact Factor
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ABSTRACT: AIMS: The anti-cancer anthracycline doxorubicin (DOX) increases the risk of cardiac damage, indicating a need to protect the heart and still allow the benefits of drug treatment. Fibroblast growth factor-2 (FGF-2) is cardioprotective against ischemia-reperfusion injury. Our aim is to investigate: (1) the ability of FGF-2 to protect against DOX-induced cardiomyocyte damage, and (2) the contribution of efflux drug transport to any increase in injury-resistance.Methods and ResultsNeonatal rat cardiomyocyte damage was assessed by measuring cell death markers and lactate dehydrogenase (LDH) activity in the culture medium. LDH activity was increased significantly after incubation with 0.5 µM DOX for 24 hours in the absence but not presence of 10 nM FGF-2; this beneficial effect of FGF-2 was blocked by FGF tyrosine kinase receptor inhibition. An increase in efflux drug transporter RNA levels was also detected after FGF-2 treatment in the presence of DOX. The beneficial effect of FGF-2 against cell damage and increased transporter RNA levels were blunted with protein kinase C (PKC) inhibition. Finally, FGF-2 stimulated efflux transport of calcein and DOX, and treatment with efflux transporter inhibitors significantly attenuated the protective effect of FGF-2 from DOX-induced injury.Conclusion(s)Administered FGF-2 increases resistance to DOX-induced cardiomyocyte damage, by a mechanism dependent on PKC as well as regulation of efflux transporter production and/or function.Cardiovascular research 01/2013; · 5.81 Impact Factor