Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer.
The aim of this study is to clarify the benefit of combination chemotherapy in gastric cancer based on a cell-signal inhibitor and an anticancer drug. Two scirrhous gastric cancer cell lines and two non-scirrhous gastric cancer cell lines were used. Five anticancer drugs (5-fluorouracil [5FU], paclitaxel, oxaliplatin, irinotecan, and gemcitabine) and four cell-signal inhibitors, mammalian target of rapamycin (mTOR) inhibitor, glycogen synthase kinase 3beta, p38alphabetaMAPK, and cyclin-dependent kinase, were used. The proliferation of cancer cells was examined by MTT assay and in vivo study. The apoptosis of cancer cells and the expression of apoptosis-related molecules were examined by flow cytometry, real-time PCR, and immunostaining. mTOR inhibitors with 5FU showed a synergistic antiproliferative effect in scirrhous gastric cancer, whereas the other signal inhibitors showed no synergistic effect with any anticancer drugs. mTOR inhibitor decreased the IC(50) of 5FU and increased the apoptosis rate in scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. The pan-caspase inhibitor, zVAD-fmk, inhibits apoptosis induced in combination with 5FU and mTOR inhibitor. mTOR inhibitor decreased dihydropyrimidine dehydrogenase, thymidylatesynthase, and bcl-2 expression, and increased caspase-3 and p21 expression of scirrhous gastric cancer cells, but did not affect those of non-scirrhous gastric cancer cells. In an in vivo study, mTOR inhibitor significantly enhanced the therapeutic efficacy of S1, an analog of 5FU. These findings suggest that mTOR inhibitor interacts with 5FU in a synergistic manner in scirrhous gastric cancer cells by the activation of the apoptosis signal. Therefore, mTOR inhibitor is a promising therapeutic agent in combination with 5FU in scirrhous gastric cancer.
Matsuzaki
Taro
T
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan.
Yashiro
Masakazu
M
Kaizaki
Ryoji
R
Yasuda
Koichi
K
Doi
Yosuke
Y
Sawada
Tetsuji
T
Ohira
Masaichi
M
Hirakawa
Kosei
K
D002293:Adenocarcinoma, Scirrhous / Q000188:drug therapy* / Q000473:pathology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
D000590:Amino Acid Chloromethyl Ketones; D047908:Intracellular Signaling Peptides and Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D005472:Fluorouracil