Potential of Anti-Leukotriene Drugs as New Therapeutic Agents for Inhibiting Cholangiocarcinoma Progression

• Published in: Molecules (Basel, Switzerland) Switzerland), 2024-07, Vol.29 (14), p.3379
• Main Authors: Kito, Yusuke, Kachi, Kenta, Yoshida, Michihiro, Hori, Yasuki, Kato, Akihisa, Sahashi, Hidenori, Toyohara, Tadashi, Kuno, Kayoko, Adachi, Akihisa, Urakabe, Kenji, Kataoka, Hiromi
• Format: Article
• Language: English
• Subjects: Acetates - chemistry; Acetates - pharmacology; Aged; Bile; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Cancer therapies; Cell adhesion & migration; Cell culture; Cell cycle; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemotherapy; Cholangiocarcinoma; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Cyclopropanes - pharmacology; Cyclopropanes - therapeutic use; cysteinyl leukotriene receptor 1; Disease Progression; drug repositioning; Drugs; Experiments; Female; Humans; Hydroxyurea - analogs & derivatives; Hydroxyurea - pharmacology; Hydroxyurea - therapeutic use; Kinases; Leukotriene Antagonists - pharmacology; Leukotriene Antagonists - therapeutic use; leukotriene D4; Leukotriene D4 - metabolism; Leukotrienes - metabolism; Male; MAP Kinase Signaling System - drug effects; Middle Aged; montelukast; Pancreatic cancer; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Quinolines - pharmacology; Receptors, Leukotriene - metabolism; Sulfides - pharmacology; zileuton
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29143379

Cholangiocarcinoma (CCA) is a cancer with a poor prognosis due to difficulties in diagnosis and limited treatment options, highlighting the urgent need for new targeted therapies. In a clinical setting, we found that leukotriene levels in bile were higher than in serum. Immunohistochemical analysis of surgically resected samples also revealed that CysLT receptor 1 (CysLTR1) was more highly expressed in CCA than in normal bile duct tissue, prompting us to investigate leukotriene as a potential therapeutic target in CCA. In vitro studies using CCA cell lines expressing CysLTR1 showed that leukotriene D4, a major ligand of CysLTR1, promoted cell proliferation, with increased phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Additionally, treatment with two clinically available anti-allergic drugs-zileuton, an inhibitor of CysLT formation, and montelukast, a CysLTR1 inhibitor-had inhibitory effects on cell proliferation and migratory capacity, accompanied by the reduced phosphorylation of AKT and ERK1/2. Furthermore, the simultaneous administration of both drugs synergistically enhanced the inhibitory effect on cell proliferation. Our study suggests that use of these drugs may represent a novel approach to treat CCA through drug repositioning.