Glyburide attenuates B(a)p and LPS-induced inflammation-related lung tumorigenesis in mice.

Mengyuan Li,Min Gao,Feifei Feng,Hua Shao,Qiao Zhang,Li Huang,Peng Zhang,Pingping Shang,Wei Wang,Hong Liu

doi:10.1002/tox.23293

Abstract

Glyburide (Gly) could inhibit NLRP3 inflammasome, as well as could be treated with Type 2 diabetes as a common medication. Despite more and more studies show that Gly could influence cancer risk and tumor growth, it remains unclear about the effect of Gly in lung tumorigenesis. To evaluate whether Gly inhibited lung tumorigenesis and explore the possible mechanisms, a benzo(a)pyrene [B(a)p] plus lipopolysaccharide (LPS)-induced non-diabetes mice model was established with B(a)p for 4 weeks and once a week (1mg/mouse), then instilled with LPS for 15 weeks and once every 3 weeks (2.5μg/mouse) intratracheally. Subsequently, Gly was administered by gavage (10μl/g body weight) 1 week before B(a)p were given to the mice until the animal model finished (when Gly was first given named Week 0). At the end of the experiment called Week 34, we analyzed the incidence, number and histopathology of lung tumors, and detected the expression of NLRP3, IL-1β, and Cleaved-IL-1β protein. We found that vehicles and tricaprylin+Gly could not cause lung carcinogenesis in the whole process. While the incidence and mean tumor count of mice in B(a)P/LPS+Gly group were decreased compared with B(a)p/LPS group. Moreover, Gly could alleviate inflammatory changes and reduce pathological tumor nest numbers compared with mice administrated with B(a)p/LPS in histopathological examination. The B(a)p/LPS increased the expression of NLRP3, IL-1β, and Cleaved-IL-1β protein significantly than Vehicle, whereas decreased in B(a)P/LPS+Gly (0.96 mg/kg) group compared with B(a)p/LPS group. Results suggested glyburide might inhibit NLRP3 inflammasome to attenuate inflammation-related lung tumorigenesis caused by intratracheal instillation of B(a)p/LPS in non-diabetes mice.

Highlights

International Agency for Research on Cancer reported that lung cancer is the primary factor of cancerrelated morbidity and death[1], the estimated new cases of lung cancer ranked second and the estimated deaths of lung cancer ranked first in United States, 2020[2]
In some early studies about cancer cells, it demonstrated that glyburide could inhibit progression in many cancers such as bladder carcinoma[18], prostate cancer[19], colon cancer[20], and liver cancer[21, 22].few in vivo studies have discussed the involvement of glyburide in lung tumorigenesis, especially in the non-diabetes mice model
The objective of our study was to investigate whether glyburide inhibit the occurrence of lung cancer, so we established the non-diabetes mice model of inflammation-related lung cancer induced by B(a)p plus LPS which have been reported in our previous study[7], and the glyburide treatment were administered from one week before the mice were intratracheal instillation with B(a)p

Summary

Introduction

International Agency for Research on Cancer reported that lung cancer is the primary factor of cancerrelated morbidity and death[1], the estimated new cases of lung cancer ranked second and the estimated deaths of lung cancer ranked first in United States, 2020[2]. LPS[7], we found that NLRP3 inflammasome activation played an important role in B(a)p plus LPSinduced inflammation-related lung tumorigenesis in mice[8]. In some early studies about cancer cells, it demonstrated that glyburide could inhibit progression in many cancers such as bladder carcinoma[18], prostate cancer[19], colon cancer[20], and liver cancer[21, 22].few in vivo studies have discussed the involvement of glyburide in lung tumorigenesis, especially in the non-diabetes mice model. We evaluated whether Gly inhibited the occurrence of lung cancer and explored the possible mechanisms in the non-diabetes mice model of inflammation-related lung cancer induced by benzo(a)pyrene [B(a)p] plus lipopolysaccharide (LPS)

Objectives

Methods

Results

Conclusion