Alprazolam Reduces Inflammatory Cytokine Production in Pancreatic Cancer–Associated Fibroblasts

Pancreatic ductal adenocarcinoma (PDAC) diagnoses are often accompanied by a number of physical and psychologic symptoms, including anxiety and depression. As a result, many patients are prescribed anxiolytics such as benzodiazepines (BZD) that have unintended effects on the tumor. Previous work from our lab has highlighted that structural differences between BZD compounds may be responsible for different clinical outcomes influenced by their effects on cancer-associated fibroblasts (CAF) within the PDAC tumor microenvironment (TME). In this study, we demonstrate that the commonly prescribed N-substituted triazolobenzodiazepine alprazolam (ALP) abrogates the production of proinflammatory cytokines, including CCL2, CXCL12, interleukin 6 (IL6), and IL8, in human CAFs. This phenotype is unique only to azole-containing BZDs, including midazolam. The ability of ALP to regulate proinflammatory cytokine production is maintained in vivo as ALP-treated mice bearing pancreatic tumors exhibited reductions in IL6 within the tumor interstitial fluid. Mechanistically, an unbiased phosphoproteomic approach revealed that ALP abrogates Toll-like receptor 4-mediated cytokine production in CAFs. These findings cumulatively support that ALP dampens CAF-mediated inflammatory signaling within the PDAC TME. SIGNIFICANCE: The data in the present study focus on the characterization of the effects of ALP on CAF output and provide a compelling basis to suggest that ALP may have a broad impact on remodeling the pancreatic cancer immune landscape and therapeutic response.