論文 - 詳細
| RRC ID | 73101 |
|---|---|
| 著者 | Oshima Y, Sano M, Kajiwara I, Ichimaru Y, Itaya T, Kuramochi T, Hayashi E, Kim J, Kitajima O, Masugi Y, Masamune A, Ijichi H, Ishii Y, Suzuki T. |
| タイトル | Midazolam exhibits antitumour and anti-inflammatory effects in a mouse model of pancreatic ductal adenocarcinoma. |
| ジャーナル | Br J Anaesth |
| 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. |
| 巻・号 | 128(4) |
| ページ | 679-690 |
| 公開日 | 2022-4-1 |
| DOI | 10.1016/j.bja.2021.12.042 |
| PII | S0007-0912(21)00873-4 |
| PMID | 35120712 |
| MeSH | Animals Carcinoma, Pancreatic Ductal* / drug therapy Carcinoma, Pancreatic Ductal* / metabolism Carcinoma, Pancreatic Ductal* / pathology Disease Models, Animal Humans Mice Mice, Transgenic Midazolam / pharmacology Midazolam / therapeutic use Pancreatic Neoplasms* / drug therapy |
| IF | 2.74 |
| リソース情報 | |
| ヒト・動物細胞 | hPSC-1(RCB3586) hPSC-5(RCB3588) hPSC-14(RCB3589) |