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.
Highlights
A major problem in cancer chemotherapy is drug resistance, to single, but to multiple drugs, which significantly compromises treatment outcomes. is phenotype is known as multidrug resistance (MDR), which is characterized by reduced intracellular drug accumulation leading to treatment failure
49 members of human ATP-binding cassette (ABC) transporter family have been discovered; among them, P-glycoprotein (P-gp, referred to ABCB1 or MDR1) and ABCG2 (MXR or breast cancer resistance protein (BCRP)) which are the important members of ABC family attribute to MDR in cancer
Evidence-Based Complementary and Alternative Medicine cells. ese energy-dependent drug efflux transporters recognize and transport various chemotherapeutic agents out of the cell and decrease intracellular drug levels and reduce their cytotoxic activity [3, 4]. erefore, inhibiting and even reversing MDR have been an important goal for oncology researches [5, 6]. e most characterized and the first described ABC transporter is P-glycoprotein, a widely expressed protein with a broad spectrum of substrates and known to be responsible for the development of chemoresistance in cancer cells
Summary
A major problem in cancer chemotherapy is drug resistance, to single, but to multiple drugs, which significantly compromises treatment outcomes. is phenotype is known as multidrug resistance (MDR), which is characterized by reduced intracellular drug accumulation leading to treatment failure. Is phenotype is known as multidrug resistance (MDR), which is characterized by reduced intracellular drug accumulation leading to treatment failure. Variety of factors causes drug resistance; among them, overexpression of ATP-binding cassette (ABC) transporters is the most frequently occurring factor [1, 2]. E most characterized and the first described ABC transporter is P-glycoprotein, a widely expressed protein with a broad spectrum of substrates and known to be responsible for the development of chemoresistance in cancer cells. P-gp is the best characterized multidrug resistance (MDR) protein, being the first human ABC transporters to be cloned. P-gp is known to transport a variety of hydrophobic drugs outside the cancer cells, conferring chemoresistance to numerous tumor types, such as gastric adenocarcinoma, breast cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, and neuroblastoma, leading to treatment failure and consequent tumor relapse
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