Matrine Suppresses Tumor Invasion In N-butyl-N-（4-hydroxybutyl） Nitrosamine-induced Urinary Bladder Cancer Via Regulation Of P16^INK4a/CyclinD1/CDK4Pathway

Objectives This study was designed to explore the effect and molecular mechanism ofmatrine on N-buthy1-N-（4-hydroxybuty1） nitrosamine（BBN）-induced bladder cancer in rats,the pathway of p16^INK4a/cyclinD1/cdk4were investigated.Methods Male Sprague-Dawley rats were randomly divided into six groups, thecontrol, BBN, celecoxib, matrine (50,100and200mg·kg^-1·d^-1) group. The bladder cancerwas induced by daily intragastric administration of N-bthyl-N-（4-hydroxybutyl） nitrosamine（BBN）(200mg·0.5ml^-1) twice a week for eight weeks in Sprague-Dawley rats. One weekbefore administration of BBN, rats were given celecoxib(500mg·kg^-1·d^-1) and different dose(50,100and200mg·kg^-1·d^-1) of matrine or saline by intragastric, whereas the group were onlyfed with saline from the beginning. Animals were sacrificed at the end of35th week,immunohistochemical method was used to detect the expression of p16^INK4a, and the proteincontent of p16^INK4a/cyclinD1/CDK4pathway in bladder tissue were measured by the methodof Western blot.Results Compared with control group, the protein level of p16^INK4awas significantlyreduced in BBN-induced bladder cancer model group（P＜0.01）, while the expression ofcyclinD1and CDK4were showed markedly increase（P＜0.01）. Matrine (200mg·kg^-1·d^-1)treatment could increase the expression of p16^INK4acompared with BBN group （P＜0.05）.Compared with BBN group, Matrine (50and200mg·kg^-1·d^-1) treatment groups could reduce the expression of cyclinD1（P＜0.05）, whereas CDK4also performed a significant decrease（P＜0.05）.Conclusions Our results suggest that matrine has an effect against the invasion ofbladder cancer. The molecular mechanism of matrine against the invasion of bladder cancerinduced by BBN is via the regulation of p16^INK4a/cyclinD1/CDK4pathway.