Amelioration of doxorubicin-induced cardiotoxicity by an anticancer-antioxidant dual-function compound, HO-3867

Doxorubicin (DOX) is a commonly-used drug for the treatment of cancer. The development of resistance to DOX is common, and high cumulative doses cause potentially lethal cardiac sideeffects. HO-3867, 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 towards cancer cells, and reduced cardiac toxicity. Combination treatment was investigated using DOX-resistant MCF-7 breast cancer cells (MCF-7 MDR) and Balb/c mice. Lower doses of HO-3867 and DOX (5 and 2.5 μM, respectively), reduce 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 of DOX. Increases in apoptotic markers, e.g. cleaved-caspase-3, and decreases in FAS and pAkt expressions were observed by western blotting. Mice treated with both HO-3867 and DOX showed significant improvement in cardiac functional parameters when compared to mice treated with DOX alone. Reduced expression of Bcl-2 and pAkt was observed in mice treated with DOX alone, while 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