Synergistic antitumor effect of dual PI3K and mTOR inhibitor NVP‑BEZ235 in combination with cisplatin on drug‑resistant non‑small cell lung cancer cell

Zhu,Hao; Shi,Yuhuan; Jiao,Xiuxiu; Yang,Gang; Wang,Rong; Yuan,Yongfang

doi:10.3892/ol.2020.12189

Synergistic antitumor effect of dual PI3K and mTOR inhibitor NVP‑BEZ235 in combination with cisplatin on drug‑resistant non‑small cell lung cancer cell

Authors:
- Hao Zhu
- Yuhuan Shi
- Xiuxiu Jiao
- Gang Yang
- Rong Wang
- Yongfang Yuan
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Affiliations: Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China
Published online on: October 5, 2020 https://doi.org/10.3892/ol.2020.12189
Article Number: 326
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cisplatin resistance is an obstacle for the effective treatment of non‑small cell lung cancer (NSCLC). The combined use of two or more chemotherapeutic agents displays advantages for the clinical treatment of drug‑resistant lung cancer. The present study aimed to assess the synergy of the dual PI3K/Akt/mTOR signaling pathway inhibitor NVP‑BEZ235 and cisplatin, a chemotherapeutic agent, on proliferation, apoptosis, cell cycle arrest and protein expression in cisplatin‑resistant NSCLC A549/diamminedichloroplatinum resistance (DDP) cells. Cell proliferation was determined by performing Cell Counting Kit 8 and colony formation assays. Combination index (CI) was used to assess the combinatorial effects of NVP‑BEZ235 and cisplatin. Cellular apoptosis and cell cycle arrest were detected via flow cytometry. Western blotting was performed to evaluate protein expression levels relative to β‑actin. Cisplatin and NVP‑BEZ235 displayed the strongest synergy (CI₅₀=0.23) at the mass ratio of 10:1. The half inhibitory concentrations of cisplatin and NVP‑BEZ235 at 10:1 were 1.53 and 0.15 µg/ml, respectively. Compared with the control group, the combination of cisplatin and NVP‑BEZ235 induced cell apoptosis and inhibited colony formation. Furthermore, compared with the control group, phosphorylation of Akt and p70S6 Kinase was significantly inhibited and cell cycle was arrested at G₀G₁ phase in the combination treatment group. The expression levels of drug efflux proteins, such as multidrug resistance‑associated protein 1 and ATP‑binding cassette sub‑family G member 2, were significantly decreased when A549/DDP cells were treated with a combination of cisplatin and NVP‑BEZ235 compared with the control group. Collectively, the present study indicated that the combined treatment of cisplatin and NVP‑BEZ235 displayed synergistic antitumor effects on drug‑resistant A549/DDP cells, by which the antiproliferative effects may occur via inhibition of the PI3K/Akt/mTOR signaling pathway and downregulation of drug efflux.

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