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Significance of c-MET overexpression in cytotoxic anticancer drug-resistant small-cell lung cancer cells.

Ozasa H, Oguri T, Maeno K, Takakuwa O, Kunii E, Yagi Y, Uemura T, Kasai D, Miyazaki M, Niimi A - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

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.

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Inhibition of c-MET activation by SU11274. Growth inhibition induced by DMSO or SU11274 (0.5, 2.0, 4.0, and 8.0 μM) in small-cell lung cancer PC-6 (□), 7-ethyl-10-hydroxycamptothesin-resistant (PC-6/SN-38) (▪) and paclitaxel-resistant (PC-6/TXL) (▪) cell lines was examined with the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay (a). The growth inhibition of SN-38 or TXL to PC-6/SN-38 or PC-6/TXL was examined with the MTS assay (b), the protein levels of c-MET, p-MET, p-ERK1/2, and p-AKT in PC-6/SN-38 and PC-6/TXL were examined (c), and at 72 h after adding none, SN-38 (5 nM), or TXL (10 nM), the levels of cleaved poly(ADP-ribose) polymerase (cleaved-PARP) were examined by Western blotting (d). *P < 0.05
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fig02: Inhibition of c-MET activation by SU11274. Growth inhibition induced by DMSO or SU11274 (0.5, 2.0, 4.0, and 8.0 μM) in small-cell lung cancer PC-6 (□), 7-ethyl-10-hydroxycamptothesin-resistant (PC-6/SN-38) (▪) and paclitaxel-resistant (PC-6/TXL) (▪) cell lines was examined with the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay (a). The growth inhibition of SN-38 or TXL to PC-6/SN-38 or PC-6/TXL was examined with the MTS assay (b), the protein levels of c-MET, p-MET, p-ERK1/2, and p-AKT in PC-6/SN-38 and PC-6/TXL were examined (c), and at 72 h after adding none, SN-38 (5 nM), or TXL (10 nM), the levels of cleaved poly(ADP-ribose) polymerase (cleaved-PARP) were examined by Western blotting (d). *P < 0.05

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).


Significance of c-MET overexpression in cytotoxic anticancer drug-resistant small-cell lung cancer cells.

Ozasa H, Oguri T, Maeno K, Takakuwa O, Kunii E, Yagi Y, Uemura T, Kasai D, Miyazaki M, Niimi A - Cancer Sci. (2014)

Inhibition of c-MET activation by SU11274. Growth inhibition induced by DMSO or SU11274 (0.5, 2.0, 4.0, and 8.0 μM) in small-cell lung cancer PC-6 (□), 7-ethyl-10-hydroxycamptothesin-resistant (PC-6/SN-38) (▪) and paclitaxel-resistant (PC-6/TXL) (▪) cell lines was examined with the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay (a). The growth inhibition of SN-38 or TXL to PC-6/SN-38 or PC-6/TXL was examined with the MTS assay (b), the protein levels of c-MET, p-MET, p-ERK1/2, and p-AKT in PC-6/SN-38 and PC-6/TXL were examined (c), and at 72 h after adding none, SN-38 (5 nM), or TXL (10 nM), the levels of cleaved poly(ADP-ribose) polymerase (cleaved-PARP) were examined by Western blotting (d). *P < 0.05
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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fig02: Inhibition of c-MET activation by SU11274. Growth inhibition induced by DMSO or SU11274 (0.5, 2.0, 4.0, and 8.0 μM) in small-cell lung cancer PC-6 (□), 7-ethyl-10-hydroxycamptothesin-resistant (PC-6/SN-38) (▪) and paclitaxel-resistant (PC-6/TXL) (▪) cell lines was examined with the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay (a). The growth inhibition of SN-38 or TXL to PC-6/SN-38 or PC-6/TXL was examined with the MTS assay (b), the protein levels of c-MET, p-MET, p-ERK1/2, and p-AKT in PC-6/SN-38 and PC-6/TXL were examined (c), and at 72 h after adding none, SN-38 (5 nM), or TXL (10 nM), the levels of cleaved poly(ADP-ribose) polymerase (cleaved-PARP) were examined by Western blotting (d). *P < 0.05
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).

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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus