W941, a new PI3K inhibitor, exhibits preferable anti-proliferative activities against nonsmall cell lung cancer with aut
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PRECLINICAL STUDIES
W941, a new PI3K inhibitor, exhibits preferable anti-proliferative activities against nonsmall cell lung cancer with autophagy inhibitors Dong Liang 1,2 & Hong-Ying Wang 3 & Shu Fan 3 & Jin Wang 1 & Ying Shen 3 & Chen-Ying Gao 1 & Man-Li Wu 1 & She-Min Lu 1 & San-Qi Zhang 3 & Wei Han 2 Received: 19 July 2019 / Accepted: 5 December 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Summary The PI3K pathway is aberrantly activated in many cancers and plays a critical role in tumour cell proliferation and survival, making it a rational therapeutic target. In the present study, the effects and the underlying mechanism of a new PI3K inhibitor, W941, were investigated in non-small-cell lung cancer (NSCLC). The results of this study showed that W941 inhibited the growth of A549 and Hcc827 cells with IC50 values of 0.12 and 0.23 μM, respectively, and that W941 markedly inhibited the growth of A549 xenograft tumours in a nude mouse model without decreasing body weight. Western blotting assays showed that W941 inhibited the phosphorylation of downstream proteins in the PI3K pathway (AKT, mTOR, p70S6K and 4EBP1) in both A549 and Hcc827 cells. In addition, after W941 treatment, a dose-dependent increase in the ratio of the LC3-II/I ratio was observed. When cells were pre-treated with chloroquine or bafilomycin A1, W941 increased the LC3-II/I ratio, suggesting that W941 acted as an autophagy inducer. Moreover, autophagy blockers enhanced apoptosis after W941 treatment, indicating that W941-induced autophagy actually protected the cells against its cytotoxicity. Our findings suggest that the combination of a PI3K inhibitor with an autophagy inhibitor might be a novel option for NSCLC treatment. Keywords PI3K inhibitor . PI3K pathway . Antitumour . Non-small-cell lung cancer . Autophagy
Introduction The PI3K/AKT/mTOR (PAM) signalling pathway has been extensively explored in oncology [1, 2]. PI3K and AKT are the kinases of the pathway that participate in cell growth and differentiation. Mammalian target of rapamycin (mTOR), a
Dong Liang and Hong-Ying Wang contributed equally to this work. * San-Qi Zhang [email protected] * Wei Han [email protected] 1
School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, People’s Republic of China
2
Department of Women’s and Children’s Health, Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden
3
Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of China
downstream protein of the PI3K signalling pathway, has emerged as a pivotal node through which cells regulate their growth and nutrient-sensing pathways to control various cellular functions, including survival, proliferation, autophagy and metabolism [3]. mTOR is a catalytic subunit of two multiprotein complexes, namely, mTOR complex 1 (mTORC1) and mTORC2 [4]. mTORC1 can be activated through the phosphoinositide 3-kinase (PI3K)/AKT signallin
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