Abstract
ABSTRACTAlthough 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.
Highlights
Cholangiocarcinoma is a malignant biliary tract tumor that carries a very poor prognosis (de Groen et al, 1999; Khan et al, 2005)
This study aimed to evaluate the therapeutic effects of rad001 and gemcitabine on cholangiocarcinoma, and elucidate the molecular and metabolic mechanisms underlying their antitumor activity
Rationale of Mammalian target of rapamycin (mTOR) inhibition for treatment of cholangiocarcinoma To assess the pharmacological effects of rad001 and gemcitabine, four treatment groups were assigned for in vitro and in vivo experiments: control, gemcitabine-treated (Gem), rad001-treated (Rad) and gemcitabine plus rad001-treated (Gem+Rad) groups
Summary
Cholangiocarcinoma is a malignant biliary tract tumor that carries a very poor prognosis (de Groen et al, 1999; Khan et al, 2005). Other therapeutic strategies, including chemotherapy, radiation therapy, transplantation and photodynamic therapy, have been developed, but none has shown significant survival benefit in patients with advanced cholangiocarcinoma (de Groen et al, 1999; Khan et al, 2005). Gemcitabine, with or without platinum compounds, is currently the most effective chemotherapy regimen for advanced biliary tract cancer, the response rate is only ∼20% (André et al, 2004; Eckel and Schmid, 2007; Valle et al, 2010, 2009). Neutralizing antibodies that target the extracellular domain of EGFR (e.g. cetuximab) have sporadically shown clinical efficacy in advanced cholangiocarcinoma (Paule et al, 2007)
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