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

• Published in: Clinical cancer research Vol. 7; no. 5; pp. 1378 - 1384
• Main Authors: VAN ACKER, Frédérique A. A, BOVEN, Epie, KRAMER, Klaas, HAENEN, Guido R. M. M, BAST, Aalt, VAN DER VIJGH, Wim J. F
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2001
• Subjects: Analysis of Variance; Animals; Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic Agents - pharmacology; Biological and medical sciences; Body Weight - drug effects; Cell Division - drug effects; Disease Models, Animal; Doxorubicin - adverse effects; Doxorubicin - therapeutic use; Drug Therapy, Combination; Drug toxicity and drugs side effects treatment; Electrocardiography - drug effects; Female; Flavonoids - pharmacology; Flavonoids - therapeutic use; Heart - drug effects; Heart Defects, Congenital - chemically induced; Heart Defects, Congenital - prevention & control; Humans; Male; Medical sciences; Mice; Mice, Inbred BALB C; Ovarian Neoplasms - drug therapy; Pharmacology. Drug treatments; Protective Agents - pharmacology; Protective Agents - therapeutic use; Toxicity: cardiovascular system; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Antineoplastic agent; Heart; Toxicity; Rodentia; Cardioprotective agent; Cardiovascular disease; Doxorubicin; Flavonoid; Prevention; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Analog; Animal; Anthracyclins; Circulatory system
• ISSN: 1078-0432; 1557-3265

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.