Enhancing the Therapeutic Efficacy of Daunorubicin and Mitoxantrone with Bavachinin, Candidone, and Tephrosin

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

doi:10.1155/2019/3291737

Enhancing the Therapeutic Efficacy of Daunorubicin and Mitoxantrone with Bavachinin, Candidone, and Tephrosin

Evid Based Complement Alternat Med. 2019 Nov 7:2019:3291737. doi: 10.1155/2019/3291737. eCollection 2019.

Authors

Sina Darzi¹, Seyed Abbas Mirzaei¹, Fatemeh Elahian¹, Sadegh Shirian^{2

3}, Amir Peymani⁴, Babak Rahmani⁵, Shaghayegh Pishkhan Dibazar⁶, Ehsan Aali⁷

Affiliations

¹ Department of Molecular Medicine, Faculty of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran.
² Department of Pathology, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.
³ Shiraz Molecular Research Center, Dr. Daneshbod Lab, Shiraz, Iran.
⁴ Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.
⁵ Department of Molecular Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.
⁶ Department of Biotechnology, Qazvin University of Medical Sciences, Qazvin, Iran.
⁷ Department of Pharmacology, Qazvin University of Medical Sciences, Qazvin, Iran.

Abstract

The capability of flavonoids in sensitizing cancer cells was demonstrated in numerous works to chemotherapy and converse multidrug resistance by modulating efflux pumps and apoptosis mechanisms. Three flavonoids, namely, bavachinin, tephrosin, and candidone, have been recently introduced to cancer treatment research presenting various activities, such as antibacterial, immunomodulatory, cell death, and anticancer. Less information exists regarding the therapeutic significance of these flavonoids in cancer treatment, especially in overcoming multidrug resistance (MDR). Here, we tempted to investigate the potency of these agents in reversing MDR by analyzing their effects as chemosensitizers on cell cytotoxicity, P-gp and ABCG2 protein expression levels, and their function on two multidrug-resistant cell lines, 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 10% (IC₁₀) of bavachinin, tephrosin, and candidone in EPG85.257RDB cells was 1588.7 ± 202.2, 264.8 ± 86.15, and 1338.6 ± 114.11 nM, respectively. Moreover, these values in MCF7/MX cell were 2406.4 ± 257.63, 38.8 ± 4.28, and 27.9 ± 5.59 nM, respectively. Expression levels of ABCG2 and P-gp were not significantly downregulated by these flavonoids. Maximum levels of daunorubicin and mitoxantrone accumulations and minimum rates of drug efflux in both cell lines were detected 48 hrs posttreatment with tephrosin and bavachinin, respectively. Chemosensitization to mitoxantrone and daunorubicin treatments was, respectively, achieved in MCF7/MX and EPG85.257RDB cells in response to IC₁₀ of bavachinin and tephrosin, independently. These effects did not follow time-dependent manner, and each flavonoid had its cell-dependent patterns. Overall, bavachinin, tephrosin, and candidone showed potency to sensitize MDR cells to daunorubicin and mitoxantrone and could be considered as attractive MDR modulators for cancer treatment. However, their action was time and cell specific.