Suppression of ABCG2 mediated MDR in vitro and in vivo by a novel inhibitor of ABCG2 drug transport

• Published in: Pharmacological research Vol. 121; pp. 184 - 193
• Main Authors: Patel, Atish, Li, Tian-Wen, Anreddy, Nagaraju, Wang, De-Shen, Sodani, Kamlesh, Gadhia, Sanket, Kathawala, Rishil, Yang, Dong-Hua, Cheng, Changmei, Chen, Zhe-Sheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-07-2017
• Subjects: Acetanilides - pharmacology; Acetanilides - therapeutic use; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - antagonists & inhibitors; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - metabolism; ATP-Binding cassette; Biological Transport - drug effects; Breast cancer resistance protein; Cell Line, Tumor; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Humans; Male; Mice, Nude; Multi-drug resistance; Neoplasms - drug therapy; Neoplasms - metabolism; Reversal; ABC; Multi-drug resistance; ABCB1; Reversal; MDR; ATP-Binding cassette; Breast cancer resistance protein; ABCG2
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2017.04.025

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Cancer is a disease whose treatment is often limited due to the development of a phenomenon known as multidrug resistance (MDR). There is an immense demand for development of novel agents that can overcome the MDR in cancer. A group of transmembrane proteins called ATP-binding cassette transporters, present ubiquitously in the human body possesses a modular architecture, contributing immensely towards the development of MDR. 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 in vitro and in vivo. CCTA-1523 (5μM) sensitized the ABCG2 overexpressing cancer cells and ABCG2 transfected cells to the substrate chemotherapeutic drugs. The reversal ability of CCTA-1523 was primarily due to the inhibition of the efflux function of ABCG2; also there was no change in the protein expression or the localization of the ABCG2 in the presence of CCTA-1523. The reversal effect of CCTA-1523 was reversible. Importantly, co-administration of CCTA-1523 restored the in vivo antitumor activity of doxorubicin in ABCG2 overexpressing tumor xenografts. Taken together, our findings indicate that CCTA-1523 is a potent, selective and reversible modulator of ABCG2 that may offer therapeutic promise for multidrug- resistant malignancies.