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

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 (1 mg/mouse), then instilled with LPS for 15 weeks and once every 3 weeks (2.5 μg/ mouse) intratracheally. Subsequently, Gly was administered by gavage (10 μl/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.

Structural Dynamics-Driven Discovery of Anticancer and Antimetastatic Effects of Diltiazem and Glibenclamide Targeting Urokinase Receptor

“…In laboratory studies, glibenclamide was reported to show contradictory influences on cancer development by interacting with the ATP-sensitive potassium channels, e.g. , sulfonylurea receptor 1, peptide transporter 1, and AKR1Cs, and to attenuate the inflammation-related tumorigenesis by inhibiting NLRP3 inflammasome . Diltiazem has been reported to enhance antitumor effects of multiple chemotherapeutics (gemcitabine, 5-fluorouracil, docetaxel, vincristine, and bortezomib) through various mechanisms including reducing drug resistance, upregulating autophagy and apoptosis-related signal pathways, and inhibition of P-glycoprotein. − Thus far, the direct antitumor or antimetastatic effect of diltiazem or glibenclamide has not been reported.…”

Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents

“…The glyburide may be beneficial to the anti-cancer effect by regulating ATP-binding cassette protein super-family and ATP-sensitive potassium channels [104] . A recent non-diabetes mice model study suggested that glyburide might inhibit NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to attenuate inflammation-related lung tumorigenesis [105] . Another case study showed that gliclazide tended to have a decreased risk of liver cancer [101] .…”

Gossypin exert lipopolysaccharide induced lung inflammation via alteration of Nrf2/HO‐1 and NF‐κB signaling pathway

“…As a result of the inflammatory response caused by LPS, pro‐inflammatory cytokines released and further generated the reactive oxygen species (ROS), which leading the induction of oxidative stress 14 . When LPS activates the host receptor toll‐Like Receptor 4 (TLR‐4), it can further trigger the release of inflammatory mediators 15 . LPS activates the TLR‐4 receptor, which further triggers the upregulation of several pathways including the activation of mitogen‐activated protein kinases (MAPKs), nuclear transcription factor κ B (NF‐κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome 12,16 .…”

“…14 When LPS activates the host receptor toll-Like Receptor 4 (TLR-4), it can further trigger the release of inflammatory mediators. 15 LPS activates the TLR-4 receptor, which further triggers the upregulation of several pathways including the activation of mitogenactivated protein kinases (MAPKs), nuclear transcription factor κ B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome. 12,16 LPS is a powerful trigger for the release of several proinflammatory cytokines, which are involved in the development of ALI.…”