We have previously reported the synergistic cytotoxic effects of
Docetaxel (TXT) and S-1 in
gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the
rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and
5-fluorouracil (5-Fu) in gastric
carcinoma cells.
Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the
cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of
5-Fu, TXT and
cisplatin were enhanced by 2 to 4 times with the concomitant administration of
rapamycin. To clarify the mechanism of the potentiation, the expression changes of the
enzymes relating
DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of
rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover,
rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal
kinase, and the activation of
caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and
5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent
gastric cancer patients.