mirogabalin and Pancreatic-Neoplasms

Mirogabalin, a selective voltage-gated calcium channel α2δ ligand, improves peripheral neuropathic pain; however, its effects on patients with cancers including pancreatic ductal adenocarcinoma (PDAC) remain unknown. We analyzed the effects of mirogabalin on a KPPC ( LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+ ) mouse model of PDAC. Six-week-old KPPC mice received oral mirogabalin (10 mg/kg/day) (n = 10) or vehicle water (n = 14) until the humane end point. Cancer-associated pain was evaluated using the scores of hunching and mouse grimace scale (MGS). Tumor status and plasma cytokine levels were determined using histopathological analysis and cytokine array, respectively. The effects of mirogabalin on the proliferative ability of PDAC cell lines were determined. The scores of the hunching and MGS improved after mirogabalin administration with a decrease in the plasma levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interferon-γ. Although no significant difference in the survival rate was observed, mirogabalin significantly increased pancreatic tumor size and proliferative index of Ki-67 and cyclins. Local arginase-1 + M2-like tumor-associated macrophages and CD31 + tumor blood vessels increased after mirogabalin administration. By contrast, the number of α-smooth muscle actin + cancer-associated fibroblasts, desmoplastic stroma, and CD8 + T cells decreased. Local myeloperoxidase + tumor-associated neutrophils and CD45R + B cells were unaltered. Mirogabalin enhanced the proliferative ability of PDAC cell lines with the upregulation of cyclins and cyclin-dependent kinases; however, it inhibited the potential of pancreatic stellate cells in vitro. Therefore, our results suggest that mirogabalin improves cancer-associated pain but enhances the proliferative potential of PDAC in vitro and in vivo.

Topics: Animals; Cancer Pain; Carcinoma, Pancreatic Ductal; Cytokines; Mice; Pancreatic Neoplasms

The prognosis of pancreatic cancer (PC) has been improved by new chemotherapy regimens (combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP)). Unfortunately, chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of these two regimens. The efficacy of pregabalin for CIPN has been reported in previous studies. However, the efficacy of mirogabalin for CIPN remains unknown. Thus, in this study, we aimed to clarify which drug (mirogabalin or pregabalin) was more valuable for improving CIPN.. A total of 163 PC patients who underwent FOLFIRINOX or GnP between May 2014 and January 2021 were enrolled. Among them, 34 patients were diagnosed with CIPN. Thirteen patients were treated with mirogabalin (mirogabalin group), and twenty-one patients were treated with pregabalin (pregabalin group). Treatment efficacy was compared between the two groups.. In both the mirogabalin group and the pregabalin group, the grade of patients with CIPN at 2, 4, and 6 weeks after the initiation of treatment showed significant improvement compared to the pretreatment grade. Notably, the rate of CIPN improvement was higher in the mirogabalin group than in the pregabalin group (2 weeks: 84.6% (11/13) vs 33.3% (7/21), P value = 0.005; 4 weeks, 6 weeks: 92.3% (12/13) vs 33.3% (7/21), P value = 0.001).. Although both mirogabalin and pregabalin were effective at improving CIPN, mirogabalin might be a suitable first choice for CIPN in PC patients.. Not applicable.

Topics: Aged; Analgesics; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Peripheral Nervous System Diseases; Pregabalin; Retrospective Studies; Treatment Outcome