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Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors.

Yamaguchi H, Takanashi M, Yoshida N, Ito Y, Kamata R, Fukami K, Yanagihara K, Sakai R - Cancer Sci. (2014)

Bottom Line: Saracatinib also effectively impaired peritoneal dissemination of Met-independent and FGFR2-independent SGC cells.Moreover, DGC cell lines exhibited nearly mutually exclusive susceptibility to Met, FGFR and Src inhibitors.These results suggest that DGC have distinct sensitivities to molecular target drugs and that targeting Src is beneficial in the treatment of DGC insensitive to Met and FGFR inhibition.

View Article: PubMed Central - PubMed

Affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

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Saracatinib impairs peritoneal dissemination of 44As3 cells. (a) Viability of 44As3 and 58As9 cells treated with various concentrations of saracatinib for 4 days. (b, c) Cells were treated with saracatinib for 2 h and subjected to immunoblot analyses with indicated antibodies. (d) 44As3Luc and 58As9 cells were intraperitoneally injected into nude mice and DMSO (vehicle) or saracatinib was administered. Representative macroscopic views of mesentery tumor nodules are shown. (e) The number of mesentery tumor nodules. Bars, SEM (n = 16 for DMSO and 18 for saracatinib in 44As3Luc; n = 8 for DMSO and 7 for saracatinib in 58As9). P < 0.001; and **P < 0.0001 by the Mann–Whitney test. (f) Representative images of mice obtained via in vivo imaging. (g) Quantitative analysis of luminescence photon counts. Bars, SD (n = 8 for DMSO and 9 for saracatinib). *P < 0.05; and **P < 0.0005 by the Mann–Whitney test. (h) Omental tumor weight in mice inoculated with 44As3Luc cells. Bars, SEM (n = 10 for DMSO and 9 for saracatinib). P = 0.3451 by the Mann–Whitney test.
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fig04: Saracatinib impairs peritoneal dissemination of 44As3 cells. (a) Viability of 44As3 and 58As9 cells treated with various concentrations of saracatinib for 4 days. (b, c) Cells were treated with saracatinib for 2 h and subjected to immunoblot analyses with indicated antibodies. (d) 44As3Luc and 58As9 cells were intraperitoneally injected into nude mice and DMSO (vehicle) or saracatinib was administered. Representative macroscopic views of mesentery tumor nodules are shown. (e) The number of mesentery tumor nodules. Bars, SEM (n = 16 for DMSO and 18 for saracatinib in 44As3Luc; n = 8 for DMSO and 7 for saracatinib in 58As9). P < 0.001; and **P < 0.0001 by the Mann–Whitney test. (f) Representative images of mice obtained via in vivo imaging. (g) Quantitative analysis of luminescence photon counts. Bars, SD (n = 8 for DMSO and 9 for saracatinib). *P < 0.05; and **P < 0.0005 by the Mann–Whitney test. (h) Omental tumor weight in mice inoculated with 44As3Luc cells. Bars, SEM (n = 10 for DMSO and 9 for saracatinib). P = 0.3451 by the Mann–Whitney test.

Mentions: The IC50 values of saracatinib for the cell growth of 44As3 and 58As9 cells were 8.2 and 30 μM, respectively (Fig.4a). Saracatinib treatment significantly decreased overall protein tyrosine phosphorylation in 44As3 but not in 58As9 cells (Fig.4b). Interestingly, saracatinib did not affect the phosphorylation of Met, ERK and Akt (Fig.4c). Saracatinib administration reduced the incidence of ascites formation and tumor dissemination to diaphragm and liver in 44As3 cells expressing luciferase (44As3Luc; Table2). Although the incidence of dissemination to mesentery was not affected much by saracatinib, a marked reduction in the number of mesentery nodules was observed (Fig.4d,e). In vivo imaging analysis confirmed that saracatinib treatment significantly reduces the growth and dissemination of 44As3Luc cells (Fig.4f,g). In contrast, neither the incidence of omental metastasis nor the growth of omental tumors was affected by saracatinib treatment (Table2 and Fig.4h). Although saracatinib tended to suppress the formation of ascites and peritoneal dissemination by 58As9 cells, the effects were more moderate (Table2 and Fig.4d,e). These data indicate that saracatinib can suppress peritoneal dissemination of SGC cells that are insensitive to Met and FGFR inhibitors.


Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors.

Yamaguchi H, Takanashi M, Yoshida N, Ito Y, Kamata R, Fukami K, Yanagihara K, Sakai R - Cancer Sci. (2014)

Saracatinib impairs peritoneal dissemination of 44As3 cells. (a) Viability of 44As3 and 58As9 cells treated with various concentrations of saracatinib for 4 days. (b, c) Cells were treated with saracatinib for 2 h and subjected to immunoblot analyses with indicated antibodies. (d) 44As3Luc and 58As9 cells were intraperitoneally injected into nude mice and DMSO (vehicle) or saracatinib was administered. Representative macroscopic views of mesentery tumor nodules are shown. (e) The number of mesentery tumor nodules. Bars, SEM (n = 16 for DMSO and 18 for saracatinib in 44As3Luc; n = 8 for DMSO and 7 for saracatinib in 58As9). P < 0.001; and **P < 0.0001 by the Mann–Whitney test. (f) Representative images of mice obtained via in vivo imaging. (g) Quantitative analysis of luminescence photon counts. Bars, SD (n = 8 for DMSO and 9 for saracatinib). *P < 0.05; and **P < 0.0005 by the Mann–Whitney test. (h) Omental tumor weight in mice inoculated with 44As3Luc cells. Bars, SEM (n = 10 for DMSO and 9 for saracatinib). P = 0.3451 by the Mann–Whitney test.
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fig04: Saracatinib impairs peritoneal dissemination of 44As3 cells. (a) Viability of 44As3 and 58As9 cells treated with various concentrations of saracatinib for 4 days. (b, c) Cells were treated with saracatinib for 2 h and subjected to immunoblot analyses with indicated antibodies. (d) 44As3Luc and 58As9 cells were intraperitoneally injected into nude mice and DMSO (vehicle) or saracatinib was administered. Representative macroscopic views of mesentery tumor nodules are shown. (e) The number of mesentery tumor nodules. Bars, SEM (n = 16 for DMSO and 18 for saracatinib in 44As3Luc; n = 8 for DMSO and 7 for saracatinib in 58As9). P < 0.001; and **P < 0.0001 by the Mann–Whitney test. (f) Representative images of mice obtained via in vivo imaging. (g) Quantitative analysis of luminescence photon counts. Bars, SD (n = 8 for DMSO and 9 for saracatinib). *P < 0.05; and **P < 0.0005 by the Mann–Whitney test. (h) Omental tumor weight in mice inoculated with 44As3Luc cells. Bars, SEM (n = 10 for DMSO and 9 for saracatinib). P = 0.3451 by the Mann–Whitney test.
Mentions: The IC50 values of saracatinib for the cell growth of 44As3 and 58As9 cells were 8.2 and 30 μM, respectively (Fig.4a). Saracatinib treatment significantly decreased overall protein tyrosine phosphorylation in 44As3 but not in 58As9 cells (Fig.4b). Interestingly, saracatinib did not affect the phosphorylation of Met, ERK and Akt (Fig.4c). Saracatinib administration reduced the incidence of ascites formation and tumor dissemination to diaphragm and liver in 44As3 cells expressing luciferase (44As3Luc; Table2). Although the incidence of dissemination to mesentery was not affected much by saracatinib, a marked reduction in the number of mesentery nodules was observed (Fig.4d,e). In vivo imaging analysis confirmed that saracatinib treatment significantly reduces the growth and dissemination of 44As3Luc cells (Fig.4f,g). In contrast, neither the incidence of omental metastasis nor the growth of omental tumors was affected by saracatinib treatment (Table2 and Fig.4h). Although saracatinib tended to suppress the formation of ascites and peritoneal dissemination by 58As9 cells, the effects were more moderate (Table2 and Fig.4d,e). These data indicate that saracatinib can suppress peritoneal dissemination of SGC cells that are insensitive to Met and FGFR inhibitors.

Bottom Line: Saracatinib also effectively impaired peritoneal dissemination of Met-independent and FGFR2-independent SGC cells.Moreover, DGC cell lines exhibited nearly mutually exclusive susceptibility to Met, FGFR and Src inhibitors.These results suggest that DGC have distinct sensitivities to molecular target drugs and that targeting Src is beneficial in the treatment of DGC insensitive to Met and FGFR inhibition.

View Article: PubMed Central - PubMed

Affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus