1. Suppression of ABCG2 mediated MDR in vitro and in vivo by a novel inhibitor of ABCG2 drug transport.
- Author
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Patel, Atish, Li, Tian-Wen, Anreddy, Nagaraju, Wang, De-Shen, Sodani, Kamlesh, Gadhia, Sanket, Kathawala, Rishil, Yang, Dong-Hua, Cheng, Changmei, and Chen, Zhe-Sheng
- Subjects
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CANCER treatment , *GENE silencing , *MULTIDRUG resistance , *MEMBRANE proteins , *DRUG development , *IN vitro studies - Abstract
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 (5 μM) 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. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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