AUTHOR=Wang Jingqiu , Wang Jing-Quan , Cai Chao-Yun , Cui Qingbin , Yang Yuqi , Wu Zhuo-Xun , Dong Xingduo , Zeng Leli , Zhao Linguo , Yang Dong-Hua , Chen Zhe-Sheng 

TITLE=Reversal Effect of ALK Inhibitor NVP-TAE684 on ABCG2-Overexpressing Cancer Cells

JOURNAL=Frontiers in Oncology

VOLUME=Volume 10 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.00228

DOI=10.3389/fonc.2020.00228

ISSN=2234-943X

ABSTRACT=Multidrug resistance (MDR) is the main reason of failure of cancer chemotherapy. Overcoming MDR mediated by overexpression of ATP binding cassette (ABC) transporters in cancer cells remains a big challenge. In this study, we explore whether NVP-TAE684, a novel ALK inhibitor which has the potential to inhibit the function of ABC transport, could reverse ABC transporter-mediated MDR.  We performed MTT assay to determine cell viability and reversal effects of NVP-TAE684 in parental and drug resistant cells.  Drug accumulation and efflux assay was carried out to evaluate the impact of NVP-TAE684 on accumulation and efflux of chemotherapeutic drugs. ABCG2-mediated ATP hydrolysis in the presence or absence of NVP-TAE684 was conducted to determine the effect of NVP-TAE684 on the ATPase activity of ABCG2 transporter. Western blot analysis and immunofluorescence assay were used to investigate protein molecules related to MDR. Additionally, the molecular interaction between NVP-TAE684 and ABCG2 transporter was identified by a docking simulation.   MTT assay showed that NVP-TAE684 significantly reversed ABCG2-mediated MDR but not ABCC1-mediated MDR. Drug accumulation and efflux studies indicated that the reversal effect of NVP-TAE684 was related to the inhibition of efflux activity of ABCG2 transporter. However, NVP-TAE684 did not alter the protein level or change the subcellular localization of ABCG2 transporter. Furthermore, ATPase analysis indicated that NVP-TAE684 stimulated ATPase activity of ABCG2 transporter in a concentration-dependent manner. Docking analysis showed that NVP-TAE684 interacts with the substrate binding sites of the ABCG2 transporter. Taken together, our study indicates that combination of NVP-TAE684 with antineoplastic drugs could attenuate ABCG2-mediated drug-resistance, which provides a new strategy for MDR cancer treatment,