Thiazole-valine peptidomimetic (TTT-28) antagonizes multidrug resistance in vitro and in vivo by selectively inhibiting the efflux activity of ABCB1

Cancer 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. Hence we made a hypothesis that TTT-28, a newly synthesized thiazole-valine peptidomimetic, could reverse ABC transporters-mediated MDR both in vitro and in vivo. MTT results showed that TTT-28 (10 microM) could nearly completely reverse the ABCB1-mediated MDR in both drug selected cells SW620/Ad300 and transfected cells HEK/ABCB1. However, T1T-28 was tested to show no reversal effect on the ABCG2-, ABCC1- and ABCC 10-mediated MDR. TTT-28 significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. No significant alteration of the expression level and localization of ABCB1 were observed after 72 h treatment of TTT-28 (10 microM). Animal study revealed that T1T-28 could inhibit the efflux activity of ABCB1, enhance the intratumoral accumulation of paclitaxel and potentiate the antineoplastic activity of paclitaxel, thereby potently inhibiting the growth of ABCB1 overexpressing tumors. But TTT-28 did not significantly affect the plasma concentrations of paclitaxel. Furthermore, TTT-28 showed no cardiotoxicity and did not cause neutropenia or thrombocytopenia in mice. In conclusion, TTT-28 is a novel selective inhibitor of ABCB1 with high efficacy and low toxicity. The identification and characterization of this novel thiazole-valine peptidomimetic will facilitate design and synthesis of a new generation of ABCB1 inhibitors, leading to further research on ABC transporters and multidrug resistance.;Keywords: multidrug resistance, ABC transporters, ABCB1, tumor xenograft, thiazolevaline peptidomimetic.