Sequential therapy with Vitamin C and Quercetin could produce oxidative stress via decreasing Nrf2 expression and improve the efficacy of chemotherapeutic drugs

Introduction & Aim. Nuclear factor erythroid 2 -related factor 2 (Nrf2), has been introduced as a sensor for electrophilic stresses. However, overexpression of Nrf2 has been reported in cancers to provide superiority for the cancer cell survival. Quercetin (QU) and vitamin C (VC) suppress Nrf2 activation and sensitizing tumor cells to anticancer agents. The aim of current study was to investigate the influence of VC+QU on the cytotoxicity profile of doxorubicin plus paclitaxel in breast cancer cells. Methods. Anti-proliferative effects of each drug were examined by MTT assay. Real time PCR applied to investigate the gene expression of Nrf2. The percentages of apoptotic cells were evaluated by flowcytometry and cell cycle analysis. Combination index were calculated using Chou–Talalay method. Results. Compared to control cells, treatment with VC+QU decreased Nrf2 expression and ROS level (p<0.05). Combination treatment with VC+QU plus drugs diminished IC50 value 2.28-7.7 comparison with the drugs alone (P<0.01). Combination therapy reduced CI value 0.6- to 12-fold compared to the drugs alone (P<0.05) and led to an induction of apoptosis at the early stages (P<0.01). The Go/G1 and S-phase was reduced after combination therapy in both MDA-MB 231 and MDA-MB 468 cells (P<0.01). Conclusion. Our study emphasizes the importance of VC+QU in combination with the cytotoxic drugs to produce a synergistic antitumor effect in breast cancer therapy. Maximum synergy was identified at doses that afford a high cancer cell inhibition beyond the one that is produced by the single agents alone and, thus, it is indicative of clinical application