Protectors against doxorubicin-induced cardiotoxicity: Flavonoids |
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Authors: | A?Bast H?Kaiserová G?J?M?den?Hartog G?R?M?M?Haenen W?J?F?van der?Vijgh |
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Institution: | (1) Department of Pharmacology and Toxicology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands;(2) Department of Biochemical Sciences, Faculty of Pharmacy, Charles University in Prague, Hradec Králové, Czech Republic;(3) Department of Medical Oncology, VU Medical Center, Amsterdam, The Netherlands;(4) Department of Pharmacology and Toxicology, Faculty of Medicine, Maastricht University, PO Box 616, 6200, MD, Maastricht, The Netherlands |
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Abstract: | Doxorubicin is a widely used anthracycline anticancer agent. Its use may cause cardiomyopathy: in fact, the development of
cumulative dose-related cardiotoxicity forms the major limitation of clinical doxorubicin use. We therefore searched for protective
agents that combine iron-chelating and oxygen radical-scavenging properties. Moreover, any novel protector should not interfere
with the cytostatic activity of doxorubicin. After extensive in vitro screening we found that flavonoids could serve this purpose. In particular 7-monohydroxyethylrutoside almost completely protected
against the negative inotropic action of doxorubicin in the electrically paced mouse left atrium model. In vivo it gave full protection at 500 mg/kg intraperitoneally against the doxorubicin-induced ST-interval lengthening in the ECG.
Moreover, this protector did not influence the antitumor effect of doxorubicin either in vitro using the human ovarian cell lines A2780 and OVCAR-3 and the human breast cancer cell line MCF-7 or in vivo in A2780 and OVCAR-3 subcutaneous xenografts in nude mice. Comparison of various iron chelators suggest that iron, in contrast
to the general assumption, might not play a crucial role in the oxidative stress-induced toxicity of doxorubicin. Moreover,
incubation of vascular endothelial cells with doxorubicin produced overexpression of adhesion molecules, which could be inhibited
by 7-monohydroxyethylrutoside. From a study in human volunteers, we conclude that an intravenous dose of 1500 mg/m2 of 7-monohydroxyethylrutoside is feasible and is safe to be investigated as protection against doxorubicin-induced cardiotoxicity. |
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Keywords: | anthracycline antioxidants cardiotoxicity doxorubicin flavonoids reactive oxygen species |
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