Abstract 2144: Next generation inhibitors to reverse ABCB1 transport mediated multidrug resistance in cancer

Abstract

Abstract The therapeutic efficacy of anticancer drugs is often limited by chemoresistance. Cancer can present intrinsic or acquired resistance to chemotherapy drugs through different mechanisms of multidrug resistance (MDR). The accelerated drug efflux facilitated by overexpression of ATP-binding cassette (ABC) transporters is one of the key mechanisms of MDR. Specifically, overexpression of ABCB1 (MDR1, P-gp) is known to be a major cause of resistance to structurally dissimilar anticancer drugs such as paclitaxel and doxorubicin. To circumvent ABC transport mediated MDR, many small molecules and kinase inhibitors have been researched and employed to retain the efficacy of the anticancer drugs. Though many small molecule inhibitors demonstrate to be useful reversal agents, understanding the mechanisms at a molecular level is important in order to design candidate drug inhibitors which are safe, selective and effective. To investigate the functional groups and molecular structures which can efficiently reverse ABCB1-mediated MDR, multiple series of thiazole-valine peptide compounds were designed, synthesized and tested in vitro. The results indicated BTT-10A was most effective in sensitizing ABCB1-mediated resistance to anticancer drugs. Both transfected and drug-selected cell lines overexpressing the ABCB1 transporter were utilized in this study. We identified BTT-10A, at nontoxic concentrations (10 μM), to have optimal MDR reversal activity through cell viability MTT cytotoxicity and reversal bioassays. BTT-10A sensitized resistant cells to the anticancer drugs in a concentration dependent manner, without downregulating the transporter expression. BTT-10A significantly increased the accumulation of ABCB1 anticancer substrate drugs by blocking the efflux function of ABCB1 transporter, as demonstrated by significant increased [3H]-paclitaxel accumulation, and increased intracellular doxorubicin accumulation through immunofluorescent detection in ABCB1 overexpressing cells. Alongside these findings, docking studies showed site-1 to be the preferable binding site for BTT-10A within the drug-binding pocket of human ABCB1 homology model. Therefore, we report that BTT-10A antagonizes MDR by inhibiting the efflux activity of the overexpressed ABCB1 transporter. These findings reveal more evidence of specific molecular structure and function of ABCB1-mediated MDR reversal agents. The therapeutic application of BTT-10A co-administered with ABCB1 substrate anticancer drugs holds promise for cancer patients resistant to specific chemotherapies, overexpressing the ABCB1 transporter. Further in vivo studies will be conducted using drug resistant xenograft models. This research will help inspire further investigations of ABC transport-mediated MDR in cancer, to find the next generation of targeted and safe reversal agents to combat chemoresistance. Citation Format: Anna Maria Barbuti, Bhargav A. Patel, Tanaji T. Talele, Zhe-Sheng Chen. Next generation inhibitors to reverse ABCB1 transport mediated multidrug resistance in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2144.