Duloxetine improves cancer-associated pain in a mouse model of pancreatic cancer through stimulation of noradrenaline pathway and its antitumor effects

Abstract

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.

Hydrogel Loaded with VEGF/TFEB‐Engineered Extracellular Vesicles for Rescuing Critical Limb Ischemia by a Dual‐Pathway Activation Strategy

“…This might be due to the reduction in energy intake as the appetite was disordered by the pain of the ischemic limb. [ 32 ] The mice in Engineered‐EV/Hydrogel group showed a significant increase in body weight compared to those in EV/Hydrogel group on days 7, 14, and 21, indicating that the improved treatment effect of hindlimb ischemia also improved the appetite (Figure S6c, Supporting Information).…”

Repositioning of duloxetine to target pancreatic stellate cells

“…Duloxetine has already been used in patients with chronic pains or painful chemotherapy-induced peripheral neuropathy ( 40 , 41 ); therefore, it is well-tolerated for clinical use. Kajiwara et al recently demonstrated that duloxetine treatment improved cancer-associated pain in a PDAC mouse model ( 42 ). They stated that duloxetine inhibited the proliferation of PCCs and CAFs, which was consistent with our report.…”

Mirogabalin improves cancer-associated pain but increases the risk of malignancy in mice with pancreatic cancer

“…15 Human pancreatic stellate cell (hPSC) lines (1, 5, and 14) were obtained from the RIKEN BioResource Research Center Cell Bank (Tsukuba, Ibaraki, Japan). 16…”