RRC ID 67146
著者 Lin G, Lin KJ, Wang F, Chen TC, Yen TC, Yeh TS.
タイトル Synergistic antiproliferative effects of an mTOR inhibitor (rad001) plus gemcitabine on cholangiocarcinoma by decreasing choline kinase activity.
ジャーナル Dis Model Mech
Abstract Although gemcitabine plus cisplatin is the gold standard chemotherapy regimen for advanced cholangiocarcinoma, the response rate has been disappointing. This study aims to investigate a novel therapeutic regimen [gemcitabine plus everolimus (rad001), an mTOR inhibitor] for cholangiocarcinoma. Gemcitabine, oxaliplatin, cetuximab and rad001 in various combinations were first evaluated in vitro using six cholangiocarcinoma cell lines. In vivo therapeutic efficacies of gemcitabine and rad001 alone and their combination were further evaluated using a xenograft mouse model and a chemically induced orthotopic cholangiocarcinoma rat model. In the in vitro study, gemcitabine plus rad001 exerted a synergistic therapeutic effect on the cholangiocarcinoma cells, irrespective of the KRAS mutation status. In the xenograft study, gemcitabine plus rad001 showed the best therapeutic effect on tumor volume change, and was associated with increased caspase-3 expression, decreased eIF4E expression, as well as overexpression of both death receptor- and mitochondrial apoptotic pathway-related genes. In a chemically induced cholangiocarcinoma-afflicted rat model, the gemcitabine plus rad001 treatment suppressed tumor glycolysis as measured by 18F-fludeoxyglucose micro-positron emission tomography. Also, increased intratumoral free choline, decreased glycerophosphocholine and nearly undetectable phosphocholine levels were demonstrated by proton nuclear magnetic resonance, supported by results of decreased choline kinase expression in western blotting. We concluded that gemcitabine plus rad001 has a synergistic antiproliferative effect on cholangiocarcinoma, irrespective of the KRAS mutation status. The antitumor effect is associated with activation of both death receptor and mitochondrial pathways, as well as the downregulation of choline kinase activity, resulting in a characteristic change in choline metabolism.
巻・号 11(8)
公開日 2018-5-14
DOI 10.1242/dmm.033050
PII dmm.033050
PMID 29666220
PMC PMC6124555
MeSH Animals Antineoplastic Combined Chemotherapy Protocols Apoptosis / drug effects Cell Cycle / drug effects Cell Line, Tumor Cell Proliferation / drug effects Cholangiocarcinoma / diagnostic imaging Cholangiocarcinoma / drug therapy* Cholangiocarcinoma / enzymology Cholangiocarcinoma / pathology* Choline / metabolism Choline Kinase / metabolism* Deoxycytidine / analogs & derivatives* Deoxycytidine / pharmacology Deoxycytidine / therapeutic use Drug Synergism Everolimus / pharmacology Everolimus / therapeutic use* Fluorodeoxyglucose F18 Gemcitabine Humans Male Metabolome Mice Positron-Emission Tomography Proton Magnetic Resonance Spectroscopy Rats, Sprague-Dawley Signal Transduction / drug effects TOR Serine-Threonine Kinases / antagonists & inhibitors* TOR Serine-Threonine Kinases / metabolism Xenograft Model Antitumor Assays
IF 4.651
リソース情報
ヒト・動物細胞 HuCCT1(RCB1960) SSP-25(RCB1293) RBE(RCB1292) YSCCC(RCB1549) TGBC24TKB(RCB1196) TFK-1(RCB2537)