Abstract 760: Suppression of ABCG2 mediated MDR in vitro and in vivo by a novel inhibitor of ABCG2 transport

Abstract

Abstract Cancer is a disease whose treatment is often limited due to the development of a phenomenon known as multidrug resistance (MDR) that is its Achilles’ heel. Hence there is an immense demand for development of novel agents that can overcome the emergence of multidrug resistance (MDR) in cancer. A group of transmembrane proteins called ABC (ATP- binding cassette) transporters, present ubiquitously in the human body possesses a modular architecture, contributing immensely towards the development of MDR in various tumor types. An analysis of structural congeners among a group of compounds led to the discovery of CCTA-1523 that could selectively reverse ABCG2-mediated MDR in cancer cells both in vitro and in vivo. CCTA-1523 at concentrations upto 5 μM sensitized the cancer cells as well as transfected cells overexpressing ABCG2 to the substrate chemotherapeutic drugs. The reversal ability of CCTA-1523 was primarily due to the inhibition of the active efflux function of the transporter; also there was no change in the protein expression of the ABCG2 transporter in the presence of CCTA-1523 at reversing concentrations. Importantly the reversal effect produced by CCTA-1523 was reversible. Co-administration of CCTA-1523 restored the in vivo antitumor activity of doxorubicin in ABCG2 overexpressing tumor xenografts without added toxicity. Taken together, our findings indicate that CCTA-1523 is a potent and reversible, modulator of ABCG2 export function that may offer therapeutic promise for multidrug- resistant malignancies. Citation Format: Atish S. Patel. Suppression of ABCG2 mediated MDR in vitro and in vivo by a novel inhibitor of ABCG2 transport. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 760. doi:10.1158/1538-7445.AM2014-760