Alprazolam Reduces Inflammatory Cytokine Production in Pancreatic Cancer-Associated Fibroblasts

Area of Science:

• Oncology
• Pharmacology
• Immunology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) patients often experience anxiety and depression, leading to prescriptions for anxiolytics like benzodiazepines.
• Benzodiazepines may have unintended effects on the tumor microenvironment (TME), potentially influenced by their chemical structure and interactions with cancer-associated fibroblasts (CAFs).

Purpose of the Study:

• To investigate the effects of alprazolam (ALP), an N-substituted triazolobenzodiazepine, on CAFs within the PDAC TME.
• To determine if ALP's effects on cytokine production are unique to azole-containing benzodiazepines and if they translate in vivo.

Main Methods:

• Human CAFs were treated with ALP to assess the production of proinflammatory cytokines (CCL2, CXCL12, IL6, IL8).
• In vivo studies involved ALP-treated mice bearing pancreatic tumors to measure IL6 levels in tumor interstitial fluid.
• Unbiased phosphoproteomics was employed to elucidate the mechanism of ALP's action on CAF signaling.

Main Results:

• Alprazolam (ALP) abrogated the production of key proinflammatory cytokines (CCL2, CXCL12, IL6, IL8) in human CAFs.
• This anti-inflammatory phenotype was observed specifically with azole-containing benzodiazepines, such as midazolam.
• In vivo, ALP treatment led to reduced IL6 levels within the tumor interstitial fluid of mice.
• Mechanistically, ALP was found to abrogate Toll-like receptor 4 (TLR4)-mediated cytokine production in CAFs.

Conclusions:

• Alprazolam (ALP) effectively dampens CAF-mediated inflammatory signaling within the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME).
• The findings highlight a potential therapeutic avenue by modulating the TME through specific benzodiazepine compounds.
• This study provides mechanistic insight into how ALP influences CAF behavior and inflammatory pathways in PDAC.