Antimicrobial Peptide Reverses ABCB1-Mediated Chemotherapeutic Drug Resistance

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.

Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids

“…As MDR inhibitors often failed due to toxicity or the occurrence of resistance, finding novel agents that overcome MDR activity is a clinical challenge [27]. AMPs were found to overcome drug resistance in OvCa cells [29] and in ABCB1-overexpressing epidermoid carcinoma cells [30]. Thus, we evaluated the activity of our peptaibols in cell lines with acquired resistance to doxorubicin (HDLM-2dx and KMH2-dx) and cisplatin (A2780cis).…”

Insights on the structure–function relationship of human multidrug resistance protein 7 (MRP7/ABCC10) from molecular dynamics simulations and docking studies

“…Moreover, information in drug binding and recognition based on structural analysis is necessary in the discovery of potential ABC transporters substrates 40 , 41 that will provide valuable references for clinicians. In the past decades, tremendous efforts have been made to circumvent the acquired chemoresistance including designing/synthesizing novel selective ABC transporter modulators, 43 , 44 , 45 , 46 , 47 repurposing small molecule drugs, 57 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 or peptides 58 , 59 , 60 as well as discovering potential ABC transporters substrates that have been used in clinic in order to prevent the decrease in therapeutic effects by adjusting treatment strategies. 42 , 61 MRP7 is an important member in ABCC subfamily with wide expression in tissues and is responsible for mediating MDR against multiple chemotherapeutic drugs.…”

Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis (C@PA)

“…The vast majority of reports specified structure-based retrospective computational approaches, in which observed biological effects of compounds were underpinned mostly through molecular docking experiments with cryo-EM structures or homology models. Most pronounced are, again, ABCB1 [37] , [38] , [39] , [40] , [41] , [42] and ABCG2 [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] . Less- or under-studied ABC transporters are barely reflected in the literature.…”