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

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. [ABSTRACT FROM AUTHOR]