Bestatin Cream Impairs Solar Simulated Light‒Driven Skin Inflammation and Skin Carcinogenesis in Mice.

Abstract

Leukotriene A4 hydrolase (LTA4H) is an enzyme that catalyzes the production of the inflammatory mediator leukotriene B4, which is involved in inflammatory responses mediated through the leukotriene B4/leukotriene B4 receptor type 1 (BLT1) signaling pathway. In this study, we investigated whether bestatin, an LTA4H inhibitor, could suppress skin acute inflammation and carcinogenesis. In the clinical sample, BLT1 was significantly induced in human skin tissues after acute solar simulated light (SSL) exposure. BLT1 and NF-κB p65 expressions were also increased in acute SSL‒induced mouse skin tissue. Furthermore, LTA4H and BLT1 were highly expressed in skin chronic inflammation and squamous cell carcinomas. More importantly, topical administration of bestatin cream dramatically inhibited BLT1 expression in acute SSL‒induced human skin tissues. BLT1 and NF-κB p65 expressions were also suppressed in acute SSL‒induced Lta4h-knockout and bestatin-treated mice skin tissues. Moreover, we conducted long-term prevention and therapeutic studies, which showed that bestatin significantly attenuated SSL-induced skin carcinogenesis. Mechanistic studies showed that bestatin inhibited skin carcinogenesis by suppressing cell proliferation and inducing cell apoptosis through LTA4H‒BLT1‒protein kinase B‒NF-κB p65 pathway. Overall, our results suggest that topical application of novel cream containing bestatin might open a helpful avenue for SSL-induced skin carcinogenesis.

• Authors: Simin Zhao, Ke Yao, Kangdong Liu, Limeng Huang, Yanan Jiang, Jian Li, Ziming Dong, Zigang Dong
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 141 Issue 11 Pg. 2699-2709.e2 (11 2021) ISSN: 1523-1747 [Electronic] United States
• PMID: 34051272 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Ltb4r1 protein, mouse
• Ointments
• Receptors, Leukotriene B4
• Transcription Factor RelA
• Epoxide Hydrolases
• Leucine
• ubenimex
• leukotriene A4 hydrolase

Topics

• Animals
• Apoptosis (drug effects)
• Carcinogenesis
• Cells, Cultured
• Dermatitis (prevention & control)
• Epoxide Hydrolases (physiology)
• Humans
• Leucine (analogs & derivatives, pharmacology)
• Mice
• Mice, Inbred BALB C
• Neoplasms, Radiation-Induced (prevention & control)
• Ointments
• Receptors, Leukotriene B4 (physiology)
• Skin Neoplasms (etiology, pathology, prevention & control)
• Sunlight (adverse effects)
• Transcription Factor RelA (physiology)