Midazolam exhibits antitumour and anti-inflammatory effects in a mouse model of pancreatic ductal adenocarcinoma

Yukino Oshima, Makoto Sano, Ichie Kajiwara, Yoshimi Ichimaru, Tomoaki Itaya, Tomoya Kuramochi, Emiko Hayashi, Jinsuk Kim, Osamu Kitajima, Yohei Masugi, Atsushi Masamune, Hideaki Ijichi, Yukimoto Ishii, Takahiro Suzuki

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the antitumour, anti-inflammatory, and analgesic effects of midazolam on LSL-KrasG12D/+;Trp53flox/flox;Pdx-1cre/+ transgenic mice with pancreatic ductal adenocarcinoma. Methods: Six-week-old transgenic mice were administered midazolam 30 mg kg−1 day−1 p.o. (n=13); midazolam 30 mg kg−1 day−1 with 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) 3 mg kg−1 day−1 i.p., a peripheral benzodiazepine receptor antagonist (n=10); or vehicle (water; n=14) until the humane endpoint. Cancer-associated pain was evaluated using hunching score and mouse grimace scale. Tumour stage and immuno-inflammatory status were determined histopathologically. Anti-proliferative and apoptotic potentials of midazolam were investigated using mouse pancreatic ductal adenocarcinoma cell lines. Results: Midazolam significantly inhibited tumour size and proliferative index of Ki-67 and cyclins in pancreatic ductal adenocarcinoma, which was blocked by administration of PK11195. Local myeloperoxidase+ tumour-associated neutrophils, arginase-1+ M2-like tumour-associated macrophages, and CD11b+Ly-6G+ polymorphonuclear myeloid-derived suppressor cells were reduced by midazolam, which was antagonised by administration of PK11195. Hunching and mouse grimace scale were improved by midazolam, whereas the scores increased with midazolam+PK11195 treatment. Plasma pro-inflammatory cytokines, such as interleukin-6 and CC chemokine ligand (CCL)2, CCL3, and CCL5, were reduced by midazolam, whereas these cytokines increased with PK11195. Midazolam inhibited pancreatic ductal adenocarcinoma proliferation through downregulation of cyclins and cyclin-dependent kinases and induced apoptosis in vitro. Conclusions: These results suggest that midazolam inhibits pancreatic ductal adenocarcinoma proliferation and local infiltration of tumour-associated neutrophils, tumour-associated macrophages, and polymorphonuclear myeloid-derived suppressor cells, thereby inhibiting pancreatic ductal adenocarcinoma progression.

Original languageEnglish
Pages (from-to)679-690
Number of pages12
JournalBritish Journal of Anaesthesia
Volume128
Issue number4
DOIs
Publication statusPublished - 2022 Apr

Keywords

  • GABA receptor
  • benzodiazepine receptor
  • midazolam
  • pancreatic ductal adenocarcinoma
  • peripheral benzodiazepine receptor
  • translocator protein

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Fingerprint

Dive into the research topics of 'Midazolam exhibits antitumour and anti-inflammatory effects in a mouse model of pancreatic ductal adenocarcinoma'. Together they form a unique fingerprint.

Cite this