Abstract
Abstract
Doxorubicin is an effective anthracycline anticancer agent for breast cancer despite its dose-limiting cardiovascular toxicity. Epicatechin is a flavonoid compound with potent antioxidant activity.. The purpose of this study is to investigate the influence of epicatechin on the cytotoxic profile of doxorubicin in breast cancer cell lines on the top of ameliorating doxorubicin induced cardiotoxicity. Rats received doxorubicin (12 mg/kg, single iv injection) with or without epicatechin (12 mg/kg, daily, oral) for 6 days then cardiac electrocardiographic was recorded. Doxorubicin administration induced cardiac ischemia which was reflected by increased QT and QTc intervals (1.76 and 1.8 folds, respectively); and increased heart rate. Epicatechin co-administration completely blocked doxorubicin induced ECG abnormalities. Epicatechin combination significantly decreased the IC50 of doxorubicin from 0.55±0.03 to 0.24±0.01; from 0.7±0.036 to 0.56±0.017, and from 0.07± 0.017 to 0.04±0.014 μM in MCF-7, T47D and MDA-MB-231 breast cancer cell lines, respectively. In addition, epicatechin significantly increased doxorubicin cytotoxicity against MCF-7 cells under hypoxic condition and decreased its IC50 from 8.9±1.2 to 6.0±1.2 μM. In MDA-MB-231, epicatechin significantly blocked p-gp efflux activity and enhanced intracellular accumulation of p-gp probe (rhodamine) by 3-4 folds at concentration range (3-100 μM). Further investigation showed that the combination of doxorubicin with epicatechin significantly increased the concentration of pro-caspase 3 compared to doxorubicin alone in T47D and MDA-MB231 cell lines. Cell death mechanism was further investigated using annexin-V/PI differential staining. Epicatechin combination did not significantly increase the percent of apoptotic or necrotic cells compared to treatment with doxorubicin alone in MCF-7 and MDA-MB-231 cells. In T47D, epicatechin combination with doxorubicin significantly increased cell apoptosis and necrosis compared to doxorubicin treatment alone from 1.5±0.5 to 4.6±0.7% and 8.0±1.7 to 12.8± 7.9%, respectively. In addition, epicatechin combination with doxorubicin decreased pro-caspase-3 concentration from 16.7±1.1 fg/cell to 9.2±2.6 fg/cell. Finally, epicatechin did not affect cell cycle distribution induced by doxorubicin. In conclusion, epicatechin significantly protected from doxorubicin induced cardiotoxicity and marginally improved its cytotoxicity against breast cancer cells.
Citation Format: Ohoud Y. Alshehri, Fahad A. Al-Abbasi, Hany M. El-Bassossy, Hossam M. Abdallah, Ahmed M. Al-Abd. Epicatechin protects from doxorubicin induced cardiotoxicity without affecting its cytotoxic profile in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 263.