PD37-10 BIOCHEMICAL VALIDATION OF PIPERLONGUMINE AS A POTENT THERAPEUTIC AGAINST NEUROENDOCRINE PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II1 Apr 2017PD37-10 BIOCHEMICAL VALIDATION OF PIPERLONGUMINE AS A POTENT THERAPEUTIC AGAINST NEUROENDOCRINE PROSTATE CANCER Kamlesh K Yadav, Khader Shameer, Jennifer Stockert, Cordelia Elaiho, Benjamin Readhead, Shalini S Yadav, Joel Dudley, and Ashutosh Tewari Kamlesh K YadavKamlesh K Yadav More articles by this author , Khader ShameerKhader Shameer More articles by this author , Jennifer StockertJennifer Stockert More articles by this author , Cordelia ElaihoCordelia Elaiho More articles by this author , Benjamin ReadheadBenjamin Readhead More articles by this author , Shalini S YadavShalini S Yadav More articles by this author , Joel DudleyJoel Dudley More articles by this author , and Ashutosh TewariAshutosh Tewari More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1572AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent studies have highlighted the existence of a highly lethal and drug-resistant variant of prostate cancer (PCa) termed neuroendocrine prostate cancer (NEPC). We have used a genomics-based drug-repositioning approach to identify piperlongumine, a natural product constituent of the fruit of the Long pepper (Piper longum), as a potential therapeutic against NEPC. The efficacy of this drug was tested in the NEPC cell line model NCI-H660 and compared to several other PCa cell lines in a modified WST-1 assay. Pre-clinical testing in mouse xenograft models of NEPC was also undertaken. Finally, the ability of piperlongumine to inhibit p-STAT3 signaling and promote apoptosis in cell lines and extracted tumors were measured by western blot analyses. METHODS PCa cell lines (LNCaP, 22Rv1, Du145, PC3, H660 and RWPE) were grown in complete media (RPM1 10%FBS, Advanced DMEM 5%FBS or Keratinocyte-SFM) and treated with piperlongumine for 3 or 7 days. IC50 values were generated from WST assay data using Prism6. Nude mice (n=5) were injected with 1.5x106 H660 cells on each flank, and intraperitoneally administered with either 2.5mg/kg piperlongumine (n=3) or DMSO (n=2) daily for 3 weeks after tumors formed 200mm3 in volume. Tumor volume was measured daily with calipers. Western blot analyses were performed on protein lysates extracted from tumors and PCa cells treated with 0-10 μM of drug. RESULTS Piperlongumine was highly effective in inhibiting the growth of H660 cells (IC50 = 0.4 μM) compared to LNCaP, 22Rv1, Du145, PC3, and RWPE cells. On average, the growth rate of untreated tumors was 2.7 times greater than those treated was piperlongumine. Treated H660 cells exhibited significant inhibition of p-STAT3 and increases in cPARP1 levels while other cell lines displayed little to no fluctuation. CONCLUSIONS Using drug-repositioning approaches we have identified a lead compound that inhibits the growth of the highly drug-resistant NEPC cell line NCI-H660. Remarkably, piperlongumine happens to be a water-soluble plant product with no known side effects. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e677-e678 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Kamlesh K Yadav More articles by this author Khader Shameer More articles by this author Jennifer Stockert More articles by this author Cordelia Elaiho More articles by this author Benjamin Readhead More articles by this author Shalini S Yadav More articles by this author Joel Dudley More articles by this author Ashutosh Tewari More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...