title: Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model.
abstract: We previously reported that withaferin A (WA), a natural compound, deters prostate cancer by inhibiting AKT while inducing apoptosis. In the current study, we examined its chemopreventive efficacy against carcinogenesis in the prostate using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Two distinct sets of experiments were conducted. To determine whether WA delays tumor progression, it was given before cancer onset, at week 6, and until week 44. To determine its effect after the onset of prostate cancer, it was given from weeks 12 to 35. In both strategies, oral administration of WA effectively suppressed tumor burden when compared to vehicle-treated animals. No toxicity was seen in treated animals at gross pathological examination. Western blot analysis and immunohistochemistry of tumor sections revealed that in TRAMP controls, AKT and pAKT were highly expressed while nuclear FOXO3a and Par-4 were downregulated. On the contrary, treated mice showed inhibition of AKT signaling and activation of FOX03a-Par-4-induced cell death. They also displayed inhibition of mesenchymal markers such as β-catenin, vimentin, and snail as well as upregulation of E-cadherin. Because expressions of the angiogenic markers factor VIII and retic were downregulated, an anti-angiogenic role of WA is suggested. Overall, our results suggest that WA could be a promising anti-cancer agent that effectively inhibits carcinogenesis of the prostate.
authors.affiliation: Department of Urology, University of Louisville, KY, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Suman
authors.affiliation: Department of Urology, University of Louisville, KY, USA.
authors.forename: Trinath P
authors.initials: TP
authors.lastname: Das
authors.affiliation: Department of Urology, University of Louisville, KY, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Moselhy
authors.affiliation: Department of Urology, University of Louisville, KY, USA.
authors.forename: Deeksha
authors.initials: D
authors.lastname: Pal
authors.affiliation: Department of Urology, University of Louisville, KY, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Kolluru
authors.affiliation: Department of Pathology, University of Louisville, KY, USA.
authors.forename: Houda
authors.initials: H
authors.lastname: Alatassi
authors.affiliation: Department of Urology, University of Louisville, KY, USA.
authors.forename: Murali K
authors.initials: MK
authors.lastname: Ankem
authors.affiliation: Department of Urology, University of Louisville, KY, USA.
authors.forename: Chendil
authors.initials: C
authors.lastname: Damodaran
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000473:pathology*; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D054358:Withanolides; C009684:withaferin A
keywords: chemoprevention; dietary agents; prostate cancer