Ttt-28, A Newly Synthesized Thiazole-Valine Peptide, Antagonizes Multidrug Resistance By Inhibiting The Efflux Activity Of The Abcb1 Transporter

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PACancer cells often exhibit either intrinsic or acquired resistance to chemotherapy through a phenomenon known as multidrug resistance (MDR). Different mechanisms contribute to the development of MDR, preeminent among them being the accelerated drug efflux mediated by overexpression of ATP-binding cassette (ABC) transporters. Currently, it has been found that some small molecule tyrosine kinase inhibitors (TKIs), such as motesanib, linsitinib, masitinib and nilotinib, were able to modulate the activity of ABC transporters. Thus, the aim of this study was to determine whether TTT-28, a newly synthesized thiazole-valine peptide, could reverse ABCB1-mediated MDR. The results showed that TTT-28 significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to its substrate anticancer drugs. Using calcein-AM efflux assay, we identified TTT-28 (IC50 = 1.0 μM) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitterion. TTT-28 significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. Furthermore, TTT-28 inhibited the photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin with IC50 = 0.75 μM and stimulated the basal ATP hydrolysis of ABCB1 in a concentration-dependent manner (EC50 ATPase = 0.027 μM). Consistent with these findings, biochemical and docking studies showed site-1 to be the preferable binding site for TTT-28 within the drug-binding pocket of human ABCB1. Therefore, we report that TTT-28 antagonizes MDR by inhibiting the efflux activity of the ABCB1 transporter. These findings reveal high clinical values for the co-administration of TTT-28 and ABCB1 substrate chemotherapeutic drugs in cancer patients that overexpress ABCB1 and stimulate further research on circumventing the ABCB1-mediated MDR in cancers.Citation Format: Yi-Jun Wang, Nagaraju Anreddy, Bhargav A. Patel, Eduardo E. Chufan, Satyakam Singh, Guan-Nan Zhang, Yun-Kai Zhang, Anna Maria Barbuti, Suresh V. Ambudkar, Tanaji T. Talele, Zhe-Sheng Chen. TTT-28, a newly synthesized thiazole-valine peptide, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1 transporter. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4422. doi:10.1158/1538-7445.AM2015-4422