Quercetin blocked doxorubicin-induced vascular damage but antagonized its antibreast cancer activity, doubling the IC50 of doxorubicin in MCF-7 cells from 0.4 to 0.8 μM.
Does quercetin protect against doxorubicin-induced vascular toxicity without compromising its antibreast cancer activity in isolated aortic rings and breast cancer cell lines?
Quercetin protects against doxorubicin-induced vascular toxicity but antagonizes its cytotoxic efficacy in certain breast cancer cell lines, suggesting caution in combining these agents.
Absolute Event Rate: 0.8% vs 0.4%
Quercetin is a naturally occurring flavonol present in many foods. Doxorubicin is an effective anticancer agent despite its dose-limiting cardiovascular toxicity. Herein, we investigated the potential protective effects of quercetin against doxorubicin-induced vascular toxicity and its effect on the therapeutic cytotoxic profile of doxorubicin in breast cancer cell lines. The incubation of isolated aortic rings with doxorubicin produced concentration-dependent exaggeration of vasoconstriction responses to phenylephrine but impaired vasodilation responses to acetylcholine. Coincubation with quercetin completely blocked the exaggerated vasoconstriction responses and the impaired vasodilation. In addition, doxorubicin incubation increased reactive oxygen species generation from the isolated aorta, while coincubation with quercetin inhibited ROS generation back to normal values. On the other hand, quercetin in combination with doxorubicin, doubled the IC50 of doxorubicin alone in MCF-7 cells from 0.4 ± 0.03 to 0.8 ± 0.06 μM. To a lesser extent, the IC50 of doxorubicin did not change after combination with quercetin in MDA-MB-231 cells. These findings indicate a significant antagonistic interaction between quercetin and doxorubicin in the aforementioned cell lines. Only in T47D cells, quercetin combination with doxorubicin was an additive interaction ( CI − value = 1.17 ). Yet, quercetin significantly impaired the immediate phase of intracellular ROS generation by doxorubicin within breast cancer cells from 125.2 ± 3.6 % to 102.5 ± 3.9 % of control cells. Using annexin-V/FITC staining technique, the quercetin/doxorubicin combination showed a significantly lower percent of apoptotic cells compared to doxorubicin alone treated cells. Cell cycle distribution in breast cancer cells was performed using DNA content flowcytometry after propidium iodide staining. Quercetin induced significant accumulation of cells in the S phase as well as in the G2/M phase within both MCF-7 and MDA-MB-231 cell lines and interfered with doxorubicin-induced cell cycle effects. Interestingly, quercetin was found to inhibit the P-glycoprotein ATPase subunit with a consequent enhanced intracellular concentration of doxorubicin in MDA-MB-231 and T47D cells. In conclusion, quercetin, despite its potent vascular protective activity against doxorubicin, was found to influence doxorubicin-induced antibreast cancer effects via pharmacodynamic as well as cellular pharmacokinetic aspects.
Henidi et al. (Fri,) conducted a other in Breast cancer and doxorubicin-induced vascular toxicity. Quercetin vs. Doxorubicin alone was evaluated on IC50 of doxorubicin in MCF-7 cells. Quercetin blocked doxorubicin-induced vascular damage but antagonized its antibreast cancer activity, doubling the IC50 of doxorubicin in MCF-7 cells from 0.4 to 0.8 μM.