title: The inhibitory effect of intravesical fisetin against bladder cancer by induction of p53 and down-regulation of NF-kappa B pathways in a rat bladder carcinogenesis model.
abstract: Intravesical chemotherapy after transurethral resection has been widely used as an adjuvant therapy to prevent recurrence and progression of superficial bladder cancer. Due to the insufficiency of the current chemotherapeutics, there is an urgent need to search for more novel, effective and safe intravesical agents. Previously, we have proved the in vitro apoptotic effects of fisetin, a dietary flavonoid, on bladder carcinoma cells. In the present study, we have further explored its intravesical efficacy and investigated the underlying mechanisms of its inhibitory effect of bladder cancer through an autochthonous rat model of bladder cancer induced by intravesical N-methyl-N-nitrosourea (MNU). We found that fisetin-induced apoptosis in bladder cancer is mediated via modulation of two related pathways: up-regulation of p53 and down-regulation of NF-κB pathway activity, causing changes in the ratio of pro- and antiapoptotic proteins. Meanwhile, administration of fisetin significantly reduced the incidence of MNU-induced bladder tumours by suppressing NF-κB activation and modulating the expression of NF-κB target genes that regulate cell proliferation and cell apoptosis. Our study suggests that the activation of p53 and inhibition of the NF-κB pathway may play important roles in the fisetin-induced apoptosis in bladder cancer. Furthermore, intravesical fisetin effectively inhibited, without any toxicity, the carcinogenesis of bladder cancer in MNU-initiated rats. These findings identify the in vivo chemopreventive efficacy of fisetin and suggest that fisetin could be used as a novel, effective and safe intravesical agent for bladder cancer.
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of the Medical College of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Weixing
authors.initials: W
authors.lastname: Qu
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Cheng
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Jiang
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zou
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Xu
authors.forename: Huacai
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D008770:Methylnitrosourea / Q000633:toxicity; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D005419:Flavonoids; D044948:Flavonols; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D008770:Methylnitrosourea; C017875:fisetin