Abstract
Abstract
The use of anti-cancer adjuvant therapy is rationalized by potentiating the efficacy and/or protecting from major side effects of chemotherapeutics. Doxorubicin is an effective anthracycline anticancer agent for breast cancer despite its dose-limiting cardiovascular toxicity. Quercetin is a flavonoid compound with potent antioxidant and cardiovascular protective activity. The purpose of this study is to investigate the influence of quercetin on the cytotoxic profile of doxorubicin in breast cancer cell lines on the top of ameliorating doxorubicin induced acute vascular toxicity. Incubation of isolated aortic rings with doxorubicin (10 uM) significantly increased contractile response of aorta to phenylephrine and decreased its relaxation response to acetylcholine. Quercetin significantly protected from doxorubicin induced vascular toxicity showing reduced contractile and increased relaxation responses of aorta to doxorubicin. On the other hand, quercetin combination significantly resulted in increasing the IC50 of doxorubicin from 0.4±0.03 to 0.8±0.06 μM in MCF-7 cells with combination index indicative of strong antagonism (CI-value = 3.2). The IC50 of doxorubicin did not change after combination with quercetin in MDA-MB-231 cells (70±10 and 76.3±4 nM, respectively), however the CI-value was 1.98 which is indicative of antagonism as well. Only in T47D cells, quercetin combination with doxorubicin was additive (CI-value = 1.17) and the IC50 of doxorubicin was significantly dropped from 0.74±0.05 to 0.36±0.003 μM. Quercetin did not affect total ROS level induced by doxorubicin, however, it significantly impaired the immediate phase of intracellular ROS generation by doxorubicin within MCF-7 cells from 125.2±3.6% to 102.5±3.9% of control cells. Yet, quercetin synergized doxorubicin cytotoxicity against MCF7 cells under hypoxic condition and significantly decreased its IC50 from 8.9±0.7 to 0.9±0.02 μM (CI-value = 0.2). Further investigation showed that the combination of doxorubicin with quercetin significantly increased the concentration of pro-caspase 3 compared to doxorubicin alone in T47D and MDA-MB-231 cell lines. Cell death mechanism was further investigated using annexin-V/PI differential staining. Quercetin combination did not significantly increase the percent of apoptotic or necrotic cells compared to treatment with doxorubicin alone in all cell lines under investigation. In addition, quercetin induced significant accumulation of cells at S-phase as well as in G2/M-phase in both MCF-7 and MDA-MB-231 cell lines. Quercetin did not affect cell cycle distribution in T47D cells. In conclusion quercetin despite its potent vascular protective activity against doxorubicin, it shows antagonistic to boarder line-additive interactions with doxorubicin in different breast cancer cell lines.
Citation Format: Hanan A. Assiri, Fahad A. Al-Abbasi, Hany M. El-Bassossy, Mohamed A. El-Moselhy, Ahmed M. Al-Abd. Quercetin protects from doxorubicin induced vascular toxicity but impairs 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 260.