Significance of c-MET overexpression in cytotoxic anticancer drug-resistant small-cell lung cancer cells.
Bottom Line: The c-MET receptor tyrosine kinase is the receptor for hepatocyte growth factor.Furthermore, the number of c-MET gene loci was increased in the resistant cells compared to the parental cells.Our results add a new strategy, the targeting of c-MET, for overcoming resistance to cytotoxic agents in small-cell lung cancer.
Affiliation: Department of Medical Oncology and Immunology, Nagoya City University, Nagoya, Japan; Department of Multidisciplinary Cancer Treatment, Kyoto University Graduate School of Medicine, Kyoto, Japan.Show MeSH
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Mentions: We examined the growth inhibition of PC-6, PC-6/SN-38, and PC-6/TXL cells by SU11274, a specific c-MET TKI.(15,29,30) SU11274 significantly inhibited the growth of the drug-resistant cells relative to the parental cells (Fig. 2a). Next, we exposed PC-6/SN-38 cells to SN-38 alone, or in combination with DMSO or SU11274 (0.5 or 2 μM concentrations). Although PC-6/SN-38 cells were resistant to SN-38 alone or in combination with DMSO, the combined treatment of SN-38 with SU11274 resulted in alteration of cytotoxicity in a dose-dependent manner (Fig. 2b). We obtained the same results in PC-6/TXL cells (Fig. 2b). We then examined downstream in the c-MET pathway. SU11274 inhibited p-MET and p-ERK1/2 in PC-6/SN-38 and PC-6/TXL cells, but not p-AKT at the 2 μM concentration (Fig. 2c). We confirmed the protein levels of cleaved-PARP in PC-6, PC-6/SN-38, and PC-6/TXL cells. The levels of cleaved-PARP protein by treatment with SN-38 and SU11274 were increased relative to that by treatment with SN-38 alone in PC-6/SN-38 cells (Fig. 2d). The cleaved-PARP levels in PC-6/SN38 cells with SU11274 alone were higher than PC6 cells (Fig. 2d). We obtained the same results in PC-6/TXL cells (Fig. 2d).
Affiliation: Department of Medical Oncology and Immunology, Nagoya City University, Nagoya, Japan; Department of Multidisciplinary Cancer Treatment, Kyoto University Graduate School of Medicine, Kyoto, Japan.