| 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 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-1.523 (2,2-dichloro-N-(3',4'-dimethoxy-[1,1'-biphenyl]-3yl) acetamide) that could selectively reverse ABCG2-mediated MDR in cancer cells both in vitro and in vivo. CCTA-1523 at concentrations up to 5 muM 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 or the localization 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. |
