The combination of everolimus and zoledronic acid increase the efficacy of gemcitabine in a mouse model of pancreatic adenocarcinoma
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Carole Vitellius1, Lionel Fizanne2, Elodie Menager-Tabourel1, Joelle Nader2, Nathalie Baize1, Margot Laly1, Emilie Lermite3, Sandrine Bertrais2 and FX Caroli-Bosc1,2
1Department of Gastroenterology, University Hospital Centre, Angers, France
2HIFIH, Laboratory, UNIV Angers, Université Bretagne Loire, Angers, France
3Department of Digestive Surgery, University Hospital Centre, Angers, France
Carole Vitellius, email: [email protected]
Keywords: everolimus; zoledronic acid; gemcitabine; pancreatic cancer
Received: October 27, 2017 Accepted: May 16, 2018 Published: June 15, 2018
Background: Gemcitabine is a standard treatment for pancreatic adenocarcinoma. Many mechanisms are involved in gemcitabine resistance, such as reduced expression of the human equilibrative nucleoside transporter 1 (hENT1) membrane transporter, deoxycytidine kinase deficiency, and changes in the signal transmission of mitogen-activity protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) pathways.
Aim: To evaluate the anti-tumor efficiency of blocking signaling pathways using combined action of gemcitabine, everolimus and zoledronic acid versus gemcitabine alone in a mouse subcutaneous xenograft.
Methods: Implantations of two human pancreatic adenocarcinoma cells lines (PANC1, K-ras mutated and gemcitabine-resistant; and BxPc3, wild-type K-ras and gemcitabine-sensitive) were performed on male athymic nude mice. The mice received different treatments: gemcitabine, gemcitabine plus everolimus, everolimus, gemcitabine plus zoledronic acid, everolimus plus zoledronic acid, or gemcitabine plus everolimus and zoledronic acid, for 28 days. We measured the tumor volume and researched the expression of the biomarkers involved in the signaling pathways or in gemcitabine resistance.
Results: In wild-type K-ras tumors, the combinations of gemcitabine plus everolimus; zoledronic acid plus everolimus; and gemcitabine plus zoledronic acid and everolimus slowed tumor growth, probably due to caspase-3 overexpression and reduced Annexin II expression. In mutated K-ras tumors, gemcitabine plus everolimus and zoledronic acid, and the combination of zoledronic acid and everolimus, decreased tumor volume as compared to gemcitabine alone, inhibiting the ERK feedback loop induced by everolimus.
Conclusion: The combination of zoledronic acid and everolimus has an antitumor effect and could increase gemcitabine efficacy.
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