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Inhibitory effect of paclitaxel followed by gefitinib on three-dimensional non-small cell lung cancer cell lines and its mechanism
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Abstract:
Objective：To explore the inhibitory effect and mechanism of sequential or combined treatment of gefitinib (G) and paclitaxel (P) on three-dimensional non-small cell lung cancer (NSCLC) cell lines. Methods: The human NSCLC cell lines A427 and Calu-3 were cultured in the ultralow attachment plates and the three-dimensional cell clusters were formed; the inhibitory effect of paclitaxel followed by gefitinib (P-G), gefitinib followed by paclitaxel (G-P), and paclitaxel combined with gefitinib (P+G) on the monolayer and three-dimensional cell lines were detected using sulforhodamine B (SRB) and Cell Titer-Blue assay, respectively; the cell cycle was detected by flow cytometry; and the expression of total EGFR and Akt protein and their phosphorylation were detected using Western blotting. Results: In the monolayer cells, the survival rates of A427 cells in the group of P-G, G-P, and P+G were (39.5±0.07)%, (57.7±003)% and (53.7±0.05)% respectively. Those of Calu-3 cells in the group of P-G, G-P and P+G were (23.9±002)%, (58.2±0.05)% and (48.8±0.07)% respectively. The inhibitory effect of P-G was the strongest (P<005). In the three-dimensional cells, the survival rates of A427 cells in the group of P-G, G-P and P+G were (19.9±2.89)%, (43.2±8.64)% and (36.6±9.79)% respectively. Those of Calu-3 cells in the group of P-G, G-P and P+G were (10.2±0.76)%, (50.0±3.45)%, (31.4±6.15)% respectively. The inhibitory effect of P-G was the strongest (P<0.05). In addition, the inhibitory effects of P-G on A427 and Calu-3 in the three-dimensional cells were stronger than those in the monolayer cells (P<0.05). The sequence of P-G resulted in an increase of subG1 proportion and arrested monolayer cells in G1 phase. The phosphorylation of EGFR and Akt was decreased in subsequent exposure to P-G. Conclusion: The sequence of P-G seems to be superior to the reverse schedule or combination in the inhibition of proliferation of NSCLC cells, based on the factors of G1 arrest and the decrease of phosphorylation of Akt and EGFR in three-dimensional cells.
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Project Supported:
Project supported by the National Natural Science Foundation of China (No. 30873023), and the Program for Young Excellent Talents in Tongji University (No. 1511219011)
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