Abstract
BackgroundGemcitabine 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.AimTo 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.MethodsImplantations 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.ResultsIn 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.ConclusionThe combination of zoledronic acid and everolimus has an antitumor effect and could increase gemcitabine efficacy.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is becoming the second leading cause of cancer-related deaths in France [1], and fourth in the world [2]
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
We hypothesized that simultaneous blocking of both signaling pathways using everolimus and zoledronic acid could increase the efficacy of gemcitabine
Summary
Pancreatic ductal adenocarcinoma (PDAC) is becoming the second leading cause of cancer-related deaths in France [1], and fourth in the world [2]. Mutated K-ras prevents the intrinsic and GAPs catalyzed hydrolysis of GTP, thereby generating permanently active RAS and constitutive activation of cell proliferative signals [13] This mutation leads to a reaction cascade marked by the successive activation of proteins involved in the MAPK pathway: Raf, MEK and ERK. It has been shown that K-Ras mutation induced feedback ERK activation contributes to the rapalog resistance in pancreatic ductal adenocarcinomas [15] and that PI3K pathway activation mediates resistance to MEK inhibitors in K-Ras mutant cancers [16]. 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 mitogenactivity protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) pathways
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