Frederine, a new and promising protector against doxorubicin-induced cardiotoxicity

The flavonoid 7-monohydroxyethylrutoside (mono-HER) Fan protect against dox orubicin-induced cardiotoxicity, A drawback of monoHER therapy would be the relatively high dose needed to obtain complete protection (500 mg/kg in mi ce). Therefore, we synthesized a series of new compounds with improved anti oxidant properties. After characterization of antioxidant activity, cardiop rotection in vitro, and possible toxic properties in hepatocytes, we select ed Frederine for additional investigations in vivo. In the present study, i t 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 dur ing 2 weeks, We recorded the electrocardiogram telemetrically in mice durin g 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 wa s found, indicating that Frederine is at least 5 times more potent than mon oHER. 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 O VCAR-3 xenografts grown in nude mice when administered 5 min before doxorub icin (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 m onoHER, Therefore, Frederine merits further investigation as a possible pro tector against doxorubicin-induced cardiotoxicity in cancer patients.