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Synergistic anti-proliferative effect of mTOR inhibitor (rad001) plus gemcitabine on cholangiocarcinoma by decreasing choline kinase activity
- Source :
- Disease Models & Mechanisms, Vol 11, Iss 8 (2018), Disease Models & Mechanisms
- Publication Year :
- 2018
- Publisher :
- The Company of Biologists, 2018.
-
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.<br />Summary: Rad001 plus gemcitabine exerts a synergistic antitumor effect on cholangiocarcinoma irrespective of KRAS mutation status, with underlying mechanisms involving activation of the death receptor, mitochondrial pathways and downregulated choline kinase activity.
- Subjects :
- Male
0301 basic medicine
Choline kinase
Proton Magnetic Resonance Spectroscopy
lcsh:Medicine
Medicine (miscellaneous)
Apoptosis
Deoxycytidine
Choline
Rats, Sprague-Dawley
Cholangiocarcinoma
Mice
chemistry.chemical_compound
0302 clinical medicine
Immunology and Microbiology (miscellaneous)
Antineoplastic Combined Chemotherapy Protocols
Phosphocholine
Cetuximab
TOR Serine-Threonine Kinases
Cell Cycle
Drug Synergism
Rad001
Chemotherapy regimen
030220 oncology & carcinogenesis
Metabolome
Signal Transduction
Research Article
lcsh:RB1-214
medicine.drug
Neuroscience (miscellaneous)
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Fluorodeoxyglucose F18
Cell Line, Tumor
lcsh:Pathology
medicine
Animals
Humans
Everolimus
neoplasms
Cell Proliferation
Cisplatin
lcsh:R
FAS
Xenograft Model Antitumor Assays
Gemcitabine
digestive system diseases
Oxaliplatin
030104 developmental biology
chemistry
Positron-Emission Tomography
Cancer research
Subjects
Details
- ISSN :
- 17548411 and 17548403
- Database :
- OpenAIRE
- Journal :
- Disease Models & Mechanisms
- Accession number :
- edsair.doi.dedup.....7612f28ce7daf2de28f57d85a4c45091