title: Amelioration of doxorubicin-induced cardiotoxicity by an anticancer-antioxidant dual-function compound, HO-3867.
abstract: Doxorubicin (DOX) is a drug commonly used for the treatment of cancer. The development of resistance to DOX is common, and high cumulative doses cause potentially lethal cardiac side effects. HO-3867 (3,5-bis(4-fluorobenzylidene)-1-[(2,2,5,5-tetramethyl-2,5-dihydro-1-hydroxy-pyrrol-3-yl)methyl]piperidin-4-one), a synthetic curcumin analog, has been shown to exhibit both anticancer and cardioprotective effects. However, its cardioprotection in the setting of a conventional cancer therapy has not been established. This work investigated the use of HO-3867 and DOX to achieve a complementary outcome, i.e., increased toxicity toward cancer cells, and reduced cardiac toxicity. Combination treatment was investigated using DOX-resistant MCF-7 breast cancer cells [MCF-7 multidrug-resistant (MDR)] and BALB/c mice. Lower doses of HO-3867 and DOX (5 and 2.5 μM, respectively) reduced viability of MCF-7 MDR cells to an extent significantly greater than that when either drug was used alone, an effect equivalent to that induced by exposure to 50 μM DOX. In normal cardiac cells, the loss of viability from combination treatment was significantly lower than that induced by 50 μM DOX. Increases in apoptotic markers, e.g., cleaved caspase-3, and decreases in fatty acid synthase and pAkt expressions were observed by Western blotting. Mice treated with both HO-3867 and DOX showed significant improvement in cardiac functional parameters compared with mice treated with DOX alone. Reduced expression of Bcl-2 and pAkt was observed in mice treated with DOX alone, whereas mice given combination treatment showed levels similar to control. The study indicates that combination treatment of HO-3867 and DOX is a viable option for treatment of cancer with reduced cardiotoxic side effects.
authors.affiliation: Davis Heart and Lung Research Institute, Department of Internal Medicine, The Ohio State University, 420 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Dayton
authors.forename: Karuppaiyah
authors.initials: K
authors.lastname: Selvendiran
authors.forename: Sarath
authors.initials: S
authors.lastname: Meduru
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: M Lakshmi
authors.initials: ML
authors.lastname: Kuppusamy
authors.forename: Shan
authors.initials: S
authors.lastname: Naidu
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020169:Caspases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010881:Piperidones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C541427:(3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one); D000970:Antineoplastic Agents; D000975:Antioxidants; D002316:Cardiotonic Agents; D016213:Cyclins; C491899:Fas protein, mouse; D010881:Piperidones; D019014:fas Receptor; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases