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Bavachinin, Candidone, and Tephrosin Improve Cytotoxicity of Daunorubicin and Mitoxantrone

Sina Darzi, Seyed Abbas Mirzaei, Fatemeh Elahian, Sadegh Shirian, Amir Peymani, Babak Rahmani, Shaghayegh Pishkhan Dibazar and Ehsan Aali

It is demonstrated that flavonoids can sensitize cancer cells to chemotherapy and inverse multidrug resistance through various mechanisms including modulating of pumps, apoptosis activation. Three flavonoids, namely Bavachinin, Candidone, and Tephrosin have recently presented in cancer research shows several effects, for example, anti-bacterial, immunomodulatory, cell death, and anti-cancer. However, the therapeutic significance of these flavonoids in cancer therapy specially to overcome Multidrug Resistance (MDR) largely unknown. Here we investigate the potency of these agents in sensitizing MDR cells. We analyzed the effect of Bavachinin, Candidone, and Tephrosin as chemosensitizer on cell cytotoxicity, P-gp and ABCG2 mRNA expression level on two multidrug resistant cells, P-gp overexpressing human gastric adenocarcinoma cell line (EPG85.257RDB) and ABCG2 overexpressing human epithelial breast cancer cell line (MCF7/MX). The inhibitory concentration of 50% (IC50) of daunorubicin in EPG85.257RDB cells in combination with IC10 of Bavachinin, Tephrosin, and Candidone were 6159 ± 948, 4186 ± 665, 730 ± 258 nM respectively, and these data in MCF7/MX cell were 1773 ± 534, 7160 ± 405 and 3340 ± 622 nM respectively. These three flavonoids dose-dependently decreased the viability of MCF7/MX and EPG85.257RDB and significantly (p<0.05) decreased IC50 of mitoxantrone and daunorubicin except Tephrosin in MCF7/MX cells. Bavachinin and Candidone were the most potent chemosensitizer in MCF7/MX and EPG85.257RDB cells respectively. Flavonoids did not reduce mRNA expression of P-gp and ABCG2 after 72 h treatment, except Candidone in EPG85.257RDB and bavachinin in MCF7/MX cells. This effect does not follow time-dependent manner, and each flavonoid has own cell-dependent patterns. Overall, Bavachinin, Tephrosin, and Candidone showed potency to sensitize MDR cells to daunorubicin and mitoxantrone.