Alprazolam reduces inflammatory cytokine production in pancreatic cancer-associated fibroblasts.

Pancreatic ductal adenocarcinoma (PDAC) diagnoses are often accompanied by a number of physical and psychological symptoms, including anxiety and depression. As a result, many patients are prescribed anxiolytics such as benzodiazepines that have unintended effects on the tumor. Previous work from our lab has highlighted that structural differences between benzodiazepine compounds may be responsible for different clinical outcomes influenced by their effects on cancer-associated fibroblasts (CAFs) within the PDAC tumor microenvironment (TME). Here, we demonstrate that the commonly prescribed N-substituted triazolobenzodiazepine alprazolam (ALP) abrogates the production of proinflammatory cytokines including CCL2, CXCL12, IL6, and IL8 in human CAFs. This phenotype is unique only to azole-containing benzodiazepines, 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 TLR4-mediated cytokine production in CAFs. These findings cumulatively support that ALP dampens CAF-mediated inflammatory signaling within the PDAC TME.