1154 8-METHYL-N-VANILLYL-6-NONENAMIDE (CAPSAICIN) INDUCES APOPTOSIS IN BLADDER CANCER CELLS INDEPENDENT OF P53 STATUS: IMPLICATION FOR THERAPY?

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 20101154 8-METHYL-N-VANILLYL-6-NONENAMIDE (CAPSAICIN) INDUCES APOPTOSIS IN BLADDER CANCER CELLS INDEPENDENT OF P53 STATUS: IMPLICATION FOR THERAPY? Nathaniel Polnaszek Nathaniel PolnaszekNathaniel Polnaszek More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.653AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Mutations in p53 are considered to be central in urothelial carcinogenesis. Missense mutations are significantly correlated with stage and grade since they form hetero oligomers and block wild type p53 binding to p53 responsive elements producing a dominant negative effect. The International Study Initiative on Bladder Cancer analyzed data sets from 25 centers and found positive p53 immunostaining in 48% of muscle invasive tumors. Retrospective analysis of patients undergoing radical cystectomy showed increased risk of recurrence and decreased overall survival with mutant p53 overexpression. Recently a more comprehensive evaluation showed that the combination of p53 gene and protein status may be linked to clinical outcome. Since p53 is involved in cell cycle checkpoint and apoptosis signaling; our objective was to target p53 function either by (a) inhibiting the activity of mutant p53 or (b) work through p53-independent mechanisms to inhibit bladder cancer cell proliferation and induce apoptosis. METHODS Human bladder cancer cells that harbor wild type p53 (RT4), or mutations in the transactivation domain (UMUC3, TCCSUP) or DNA binding domain (T24) were grown as per vendor recommendations. Cells were treated with increasing doses of capsaicin (16, 32 and 64 fÝM) and proliferation inhibition, cell cycle progression, apoptosis induction and the mechanism of capsaicin-induced apoptosis were determined. RESULTS Capsaicin caused a dose responsive inhibition of proliferation and the IC50 was not dependent on p53 status. At low doses of capsaicin cells were arrested in G1 phase and in G2 phase at high doses. We also found a dose-dependent increase in induction of apoptosis following capsaicin treatment that was independent of the status of p53. Examination of the mechanism of apoptosis induction shows that capsaicin disrupts the interactions between proteins in the death receptor pathway and there is crosstalk between the death receptor and mitochondrial pathway in the more advanced bladder cancer cells. CONCLUSIONS This study demonstrates that capsaicin could be a good candidate therapeutic agent for bladder cancer given the putative oncogenic role for p53 in bladder cancer these results are highly significant. San Antonio, TX© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e447 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nathaniel Polnaszek More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...