No abstract

Epicatechin (EPI) has a well known and robust antioxidant properties which could alleviate drug-induced cardiovascular toxicities. On the other side, Doxorubicin (DOX) is a cornerstone anticancer drug used to treat breast cancer. However, DOX-induced cardiovascular complications might limit its treatment course continuation. Herein, we evaluated cardiovascular protective effects of EPI against DOX in-vivo and ex-vivo using isolated aortic ring preparation; meanwhile we assessed the potential ameliorating effects of EPI against DOX-induced cytotoxicity in breast cancer cells. Animals were given DOX (12 mg/kg, single IV injection) which induced cardiac ischemia appeared as increased QT and QTc intervals (1.8 folds for both). EPI (12 mg/kg, orally for 6 days) completely aborted DOX-induced cardiac ischemia and corrected all ECG abnormalities. Using isolated aortic ring preparation, DOX (10µM) impaired aortic ring vasodilatation and induced excessive vasoconstriction. Co-incubation of EPI (10µM) with DOX (10µM) entirely blocked DOX-induced impaired aortic ring vasodilatation, without affecting DOX-induced elevated vasoconstriction. EPI (10µM) combination with DOX in MDA-MB-231, MCF7 and T47D breast cancer cells significantly decreased the IC50‘s from 70.0±17.3 to 44.0±14.0 nM, from 554.0±30 to 240.0±10.0 nM and from 700.0±36.0 to 561.0±170 nM, respectively. Under hypoxic condition, EPI (10µM) significantly increased DOX cytotoxicity against MCF-7 cells and decreased its IC50 from 8.9±1.2 to 6.1±1.9 μM. This effect could be partially attributed to the inhibitory effect of EPI to P-glycoprotein (P-gp) and related efflux protein which would enhance DOX intracellular concentration. EPI increased the intracellular accumulation of rhodamine (P-gp probe) within MDA-MB-231 cells by 3-4 folds at concentration range from 3 to 100 μM. Moreover, EPI combination with DOX significantly increased cell apoptosis and necrosis assessed by annexin-V/FITC. However, EPI did not influence DOX effect on cell cycle distribution. In conclusion, EPI possesses potential cardiovascular protective effects against DOX. Meanwhile, EPI does not interfere with DOX-induced cytotoxic profile against breast cancer cells. Citation Format: Ohoud Y. Alshehri, Fahad A. Alabbasi, Islam F. Mahmoud, Alaa T. Abu-Sharib, Hany M. El-Bassossy, Hossam A. Abdallah, Ahmed M. Al-Abd. Epicatechin alleviates DOX-induced cardiovascular toxicity and improves its cytotoxic profile against breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4930.