Abstract
Multidrug resistance (MDR) of tumor cells to chemotherapeutic agents is the main reason for the failure of cancer chemotherapy. Overexpression of ABCB1 transporter that actively pumps various drugs out of the cells has been considered a major contributing factor for MDR. Over the past decade, many antimicrobial peptides with antitumor activity have been identified or synthesized, and some antitumor peptides have entered the clinical practice. In this study, we report that peptide HX-12C has the effect of reversing ABCB1-mediated chemotherapy resistance. In ABCB1-overexpressing cells, nontoxic dose of peptide HX-12C inhibited drug resistance and increased the effective intracellular concentration of paclitaxel and other ABCB1 substrate drugs. The mechanism study showed that peptide HX-12C stimulated ABCB1 ATPase activity without changing the expression level and localization patterns of ABCB1. Molecular docking predicted the binding modes between peptide HX-12C and ABCB1. Overall, we found that peptide HX-12C reverses ABCB1-mediated MDR through interacting with ABCB1 and blocking its function without affecting the transporter’s expression and cellular localization. Our findings suggest that this antimicrobial peptide may be used as a novel prospective cancer therapeutic strategy in combination with conventional anticancer agents.
Highlights
Cancer remains the main cause of human death (Torre et al, 2015; Siegel et al, 2020)
The secondary structure was predicted by the secondary structure prediction service (HeliQuest), and the secondary structure of the antibacterial peptide was analyzed by circular dichroism
To investigate the possible mechanism of the sensitivity of ABCB1-overexpressed cells to anticancer drugs caused by peptide HX-12C, we studied the effect of peptide HX-12C on the expression level and cellular localization of the ABCB1 protein in ABCB1-overexpressing cells (KB-C2) and their parental cells (KB-3-1)
Summary
Cancer remains the main cause of human death (Torre et al, 2015; Siegel et al, 2020). Among all kinds of cancer treatments, chemotherapy is still the mainstay therapy for most cancers in clinic (Dong et al, 2018b). New anticancer drugs and chemotherapy protocols are being constantly found or optimized, the therapeutic efficacy has not significantly improved. This is mainly because most patients will develop resistance to conventional and targeted chemotherapy during the course of their treatment. Drug resistance has been considered a major obstacle to the successful treatment of cancers (Holohan et al, 2013; Tsukamoto et al, 2019).
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