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

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.

Candidone Inhibits Migration and Invasion, and Induces Apoptosis in HepG2 Cells

“…[15][16][17][18] It has been reported that candidone showed antitumor effect on human cholangiocarcinoma (CCA) cells and sensitized MDR cells to daunorubicin and mitoxantrone. [19][20] In the current study, Candidone was also found to inhibit both the migration and invasion abilities of HepG2 cells. Figure 2A shows that candidone at concentration 100 µM induced cell death more than 50%.…”

Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles

“…Moreover, dihydromyricetin, a natural flavonoid from the leaves of Vitis heyneana , reversed MRP2-induced MDR by preventing NF-κB-Nrf2 signaling in colorectal cancer HCT116/OXA and HCT8/VCR cell lines [ 114 ]. Also, bavachinin, tephrosin, and candidone sensitized MDR MCF7/MX and EPG85.257RDB cells to daunorubicin and mitoxantrone [ 115 ].…”

Combined Treatment of Dendrosomal-Curcumin and Daunorubicin Synergistically Inhibit Cell Proliferation, Migration and Induce Apoptosis in A549 Lung Cancer Cells

“…To overcome these problems, the application of DNR in combination with other chemotherapy drugs reduces drug resistance and intensifies the toxicity of the combined drugs on cancer cells compared to DNR alone. 12 DNR anticancer function is the result of its incorporation into the minor groove of DNA, resulting in an arrest in replication. 10 In addition, DNR inhibits the topoisomerase II enzyme by stabilizing the interaction of the enzyme and DNA.…”

“…Likewise, recent studies have reported the therapeutic effect of DNR in combination with other agents. 12 …”