GSK1904529A, a Potent IGF‐IR Inhibitor, Reverses MRP1‐Mediated Multidrug Resistance. Issue 10 (3rd May 2017)

• Record Type: Journal Article
• Authors: Gupta, Pranav; Xie, Meina; Narayanan, Silpa; Wang, Yi‐Jun; Wang, Xiu‐Qi; Yuan, Timothy; Wang, Ziyue; Yang, Dong‐Hua; Chen, Zhe‐Sheng
• Is Part Of: Journal of cellular biochemistry. Volume 118:Issue 10(2017)
• Page Start: 3260
• Page End: 3267
• Publication Date: 2017-05-03
• Subjects: GSK1904529A -- ABC TRANSPORTERS -- MRP1 -- MULTIDRUG‐RESISTANCE; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.25975
• Languages: English
• ISSNs: 0730-2312

Abstract

ABSTRACT: Overexpression of multidrug‐resistant efflux transporters is one of the major causes of chemotherapy failure. MRP1, a 190 kDa efflux transporter, confers resistance to a wide of range of chemotherapeutic drugs. Here we study the cellular effects of GSK1904529A in reversing MRP1‐mediated drug resistance. Cytotoxicity of GSK1904529A was determined by MTT assay. Reversal effects of GSK1904529A in combination with MRP1 substrates were determined. The intracellular accumulation and efflux of MRP1 substrate was measured by scintillation counter and protein expression was determined by Western blotting analysis. Cell cycle effects of GSK1904529A in combination with MRP1 substrates were determined by flow cytometric analysis. GSK1904529A, at non‐toxic concentrations, enhanced the cytotoxicity of MRP1 substrates in HEK293/MRP1 cells. Furthermore, GSK1904529A increased the intracellular accumulation of [ 3 H]‐vinblastine by inhibiting the efflux function of MRP1. GSK1904529A did not alter the expression level of MRP1, induced a G0/G1 phase cell cycle arrest. Our results indicated that GSK1904529A significantly increased the sensitivity of MRP1 overexpressing cells to chemotherapeutic agents. Furthermore, GSK1904529A enhanced the efficacy of chemotherapeutic drugs that are substrates of MRP1. J. Cell. Biochem. 118: 3260–3267, 2017. © 2017 Wiley Periodicals, Inc. Abstract : GSK1904529A, a potent IGF‐IR inhibitor, sensitizes MRP1 overexpressing cells to the substrates of MRP1. GSK1904529A inhibits the efflux of substrates of MRP1 and causes a cell cycle arrest in G0/G1 phase.