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Anti-Allergic Drug Suppressed Pancreatic Carcinogenesis via Down-Regulation of Cellular Proliferation.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Jul 12; Vol. 22 (14). Date of Electronic Publication: 2021 Jul 12. - Publication Year :
- 2021
-
Abstract
- Pancreatic cancer is a fatal disease, and thus its chemoprevention is an important issue. Based on the recent report that patients with allergic diseases have a low risk for pancreatic cancer, we examined the potential chemopreventive effect of anti-allergic agents using a hamster pancreatic carcinogenesis model. Among the three anti-allergic drugs administered, montelukast showed a tendency to suppress the incidence of pancreatic cancer. Further animal study revealed a significantly decreased incidence of pancreatic cancer in the high-dose montelukast group compared with controls. The development of the pancreatic intraepithelial neoplasia lesions was also significantly suppressed. The Ki-67 labeling index was significantly lower in pancreatic carcinomas in the high-dose montelukast group than in controls. In vitro experiments revealed that montelukast suppressed proliferation of pancreatic cancer cells in a dose-dependent manner with decreased expression of phospho-ERK1/2. Montelukast induced G1 phase arrest. Conversely, leukotriene D <subscript>4</subscript> (LTD <subscript>4</subscript> ), an agonist of CYSLTR1, increased cellular proliferation of pancreatic cancer cells with an accumulation of phospho-ERK1/2. In our cohort, pancreatic ductal adenocarcinoma patients with high CYSLTR1 expression showed a significantly unfavorable clinical outcome compared with those with low expression. Our results indicate that montelukast exerts a chemopreventive effect on pancreatic cancer via the LTD <subscript>4</subscript> -CYSLTR1 axis and has potential for treatment of pancreatic carcinogenesis.
- Subjects :
- Animals
Carcinogens toxicity
Cricetinae
Humans
Male
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms pathology
Tumor Cells, Cultured
Acetates pharmacology
Anti-Asthmatic Agents pharmacology
Cell Proliferation
Cyclopropanes pharmacology
Leukotriene D4 metabolism
Nitrosamines toxicity
Pancreatic Neoplasms drug therapy
Quinolines pharmacology
Receptors, Leukotriene metabolism
Sulfides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 34299067
- Full Text :
- https://doi.org/10.3390/ijms22147444