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Frederine, a New and Promising Protector Against Doxorubicin-induced Cardiotoxicity

Department of Medical Oncology, University Hospital Vrije Universiteit, 1081 HV Amsterdam [F. A. A. v. A., E. B., W. J. F. v. d. V.]; Department of Pharmacology and Toxicology, University Maastricht, 6200 MD Maastricht [F. A. A. v. A., G. R. M. M. H., A. B.]; and Department of Safety and Environmental Affairs, Vrije Universiteit, 1081 HV Amsterdam [K. K.], the Netherlands

The flavonoid 7-monohydroxyethylrutoside (monoHER) can protect against doxorubicin-induced cardiotoxicity. A drawback of monoHER therapy would be the relatively high dose needed to obtain complete protection (500 mg/kg in mice). Therefore, we synthesized a series of new compounds with improved antioxidant properties. After characterization of antioxidant activity, cardioprotection in vitro, and possible toxic properties in hepatocytes, we selected Frederine for additional investigations in vivo. In the present study, it was found that this compound did not induce weight loss or (gross) organ changes in mice in a treatment schedule of 170 mg/kg i.p., 5 times/week during 2 weeks. We recorded the electrocardiogram telemetrically in mice during and 2 weeks after the combined treatment with doxorubicin (4 mg/kg, i.v.) and 5 times Frederine (68 mg/kg, i.p.; equimolar to 100 mg/kg monoHER) for 6 weeks. Complete protection against doxorubicin-induced cardiotoxicity was found, indicating that Frederine is at least 5 times more potent than monoHER. Frederine did not have a negative influence on the antiproliferative effects of doxorubicin on A2780, OVCAR-3, and MCF-7 cells in vitro and on OVCAR-3 xenografts grown in nude mice when administered 5 min before doxorubicin (8 mg/kg i.v.) and 4 days thereafter with an interval of 24 h. It can be concluded that we succeeded in designing a better cardioprotector than monoHER. Therefore, Frederine merits further investigation as a possible protector against doxorubicin-induced cardiotoxicity in cancer patients.

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