Synergistic antiproliferative effects of an mTOR inhibitor (rad001) plus gemcitabine on cholangiocarcinoma by decreasing choline kinase activity

Gigin Lin, Kun Ju Lin, Frank Wang, Tse Ching Chen, Tzu Chen Yen, Ta Sen Yeh*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

8 Scopus citations

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 cholangiocarcinomaafflicted 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.

Original languageEnglish
Article numberdmm033050
JournalDMM Disease Models and Mechanisms
Volume11
Issue number8
DOIs
StatePublished - 08 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018. Published by The Company of Biologists Ltd.

Keywords

  • Cholangiocarcinoma
  • Choline kinase
  • FAS
  • Gemcitabine
  • Rad001

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