Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. Patients with inoperative PDAC require effective chemotherapy and pain control to increase their quality of life. We investigated whether duloxetine, a serotonin–noradrenaline reuptake inhibitor, improves quality of life in a KPPC (LSL-Kras G12D/+ ;Trp53 flox/flox ;Pdx1-cre) mouse model of PDAC. Six-week-old KPPC mice were orally administered 4 mg/kg/d duloxetine (n = 12); 4 mg/kg/d duloxetine with 0.15 mg/kg/d atipamezole, a synthetic α2 adrenergic receptor antagonist (n = 9); or vehicle water (n = 11). Body weight and food intake were measured daily, and cancer pain was evaluated by the hunching score and mouse grimace scale. At the endpoint, the tumor status, angiogenesis, and immunoinflammatory condition were analyzed. The pain level using the hunching and mouse grimace scale scores improved by duloxetine in KPPC mice (P < 0.01), whereas the scores that had been reduced by duloxetine were elevated by administration of atipamezole. Kaplan–Meier analysis demonstrated that duloxetine-treated mice had significantly prolonged survival (P < 0.05) with delayed appetite loss, cachexia, and body weight loss. Duloxetine inhibited the proliferation of PDAC cells and cancer-associated fibroblasts in vivo with a shift into an antitumor immunoinflammatory condition and the corresponding plasma cytokine levels. The migrative/invasive potentials of PDAC were inhibited by duloxetine in vitro. Meanwhile, atipamezole did not inhibit the antitumor effects of duloxetine in vitro and in vivo. Therefore, our results indicate that duloxetine mainly improves cancer-associated pain by enhancement of the noradrenergic pathway rather than the serotonergic pathway, whereas duloxetine modulates antitumor effects on PDAC without involvement of the noradrenergic pathway.

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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high invasive and metastatic potential. We generated a spontaneous PDAC mouse model and examined the therapeutic potential of indirubin 3′-oxime (Indox) against PDAC bearing mouse in vivo. METHODS: Randomized 3-month-old LSL-KrasG12D/+;Trp53flox/+;Pdx-1-cre (KPCflox) mice were intraperitoneally injected with 40 mg/kg Indox (n = 9) or a vehicle (n = 10) twice a week. At the end point, tumor status including proliferation, direct invasion, and distant metastasis was analyzed histopathologically. The inhibitory potentials of Indox for proliferation, migration/invasion, and the phosphorylation of target molecules were determined in KPCflox-derived PDAC cells in vitro. RESULTS: Prolonged survival by Indox via intraperitoneal administration was observed in the KPCflox mice. Indox inhibited tumor proliferation accompanied with low levels of nuclear phosphorylated cyclin-dependent kinase (p-CDK) and cyclin B1 in vivo. Furthermore, Indox inhibited the migration/invasive activities of PDAC via down-regulation of matrix metalloproteinase (MMP)-9 in vitro and in vivo. Antibody array and immunoblotting analysis revealed that Indox inhibited the phosphorylation of multiple molecules, including key upstream proteins of MMP-9 in RAF/extracellular signal-regulated kinase (ERK), AKT, and stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK) pathways. CONCLUSION: Indox inhibited the proliferative, invasive, and metastatic potentials of PDAC in vitro and in vivo. Therefore, Indox could a therapeutic candidate for treating spontaneously occurring PDAC via blocking the RAF/ERK, AKT and SAPK/JNK pathways.

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Supplemental Digital Content is Available in the Text.Mirogabalin improves cancer-associated pain but enhances the proliferative potential of pancreatic ductal adenocarcinoma in vivo and in vivo.