Panel B shows the isobologram result of drug combination between ATRA and imatinib. This combination resulted in additive effect. Cytotoxic effect of combination with ATRA and imatinib The result of isobologram was showed in Figure 5B. All data points in the combination fell within the envelope of additivity, the area surrounded by the three lines, suggesting that this combination gave additive effect. Discussion ATRA have been reported to show therapeutic Akt inhibitor effect on breast and ovarian cancers and

APL [28]. However, for the first time we have demonstrated that ATRA suppressed the cell proliferation and induced apoptosis in GIST-T1 cells, suggesting anti-cancer effect of ATRA on GISTs. The cell death inducing mechanism by ATRA www.selleckchem.com/products/dabrafenib-gsk2118436.html in cancers has not yet been

fully clarified. In this report we have shown that apoptosis induced by ATRA in GIST-T1 cells are regulated at least by the down-regulation of survivin and up-regulation of Bax (Figure 3A and 3B). Even though XIAP and survivin belong to the same family of apoptotic inhibitors, it is likely that ATRA effected quite differently on expression of XIAP and survivin. Survivin was suppressed in a time dependent manner whereas XIAP was not suppressed by ATRA treatment (Figure 3C). It is likely that survivin may be a target molecule that plays an important role in ATRA-induced apoptosis in GIST-T1 cells. Further studies are definitely necessary for better understanding of the apoptosis-inducing mechanism by ATRA in GIST-T1 cells. GISTs can be successfully treated with imatinib with the response rate of up to 85% [15, 29, 30]. However, after a median of 2 years of treatment with imatinib, resistance can develop [15]. The effect of imatinib is mainly due to the suppression of KIT activity. In this study, we found that the suppression of KIT activity (Figure 4A) was also obtained by ATRA treatment. Moreover, we have demonstrated else that combination of ATRA and

imatinib showed additive effect (Figure 5B) by isobologram, suggesting that the combination of ATRA and imatinib would be a novel therapeutic potential for GISTs. The scratch assay result (Figure 5A) also suggested the useful of ATRA to prevent the invasion or metastasis of GIST cells. In conclusion, we have demonstrated that ATRA had an ability to inhibit the cell proliferation and migration, inducing apoptosis in GIST-T1 cells. Thus ATRA can have a potential for novel therapeutic agent for GISTs. Since the combination of ATRA and imatinib showed additive effect on GIST-T1 cells, ATRA may be used in combination with imatinib for GISTs treatment. Acknowledgements This work was supported by the Japan Foundation for Promotion of International Medical Research Co-operation (JF-PIMRC). References 1. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM: Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal.