403 GROWTH INHIBITION OF PROSTATE CANCER XENOGRAFTS UPON CHRONIC TREATMENT WITH VALPROIC ACID BY CELL CYCLE ARREST AND INHIBITION OF TUMOR VASCULATURE (2011)

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011403 GROWTH INHIBITION OF PROSTATE CANCER XENOGRAFTS UPON CHRONIC TREATMENT WITH VALPROIC ACID BY CELL CYCLE ARREST AND INHIBITION OF TUMOR VASCULATURE Abhinav Sidana, Muwen Wang, Shabana Shabbeer, Wasim H. Chowdhury, George Netto, Shawn E. Lupold, Michael Carducci, and Ronald Rodriguez Abhinav SidanaAbhinav Sidana Cincinnati, OH More articles by this author , Muwen WangMuwen Wang Jinan, China, People's Republic of More articles by this author , Shabana ShabbeerShabana Shabbeer Baltimore, MD More articles by this author , Wasim H. ChowdhuryWasim H. Chowdhury Baltimore, MD More articles by this author , George NettoGeorge Netto Baltimore, MD More articles by this author , Shawn E. LupoldShawn E. Lupold Baltimore, MD More articles by this author , Michael CarducciMichael Carducci Baltimore, MD More articles by this author , and Ronald RodriguezRonald Rodriguez Baltimore, MD More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.492AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Valproic Acid (VPA), a histone deacetylase inhibitor, has been demonstrated to cause a marked decrease in proliferation of prostate cancer cells in vitro and a significant reduction in tumor volume in vivo. VPA has been shown in vitro to re-express repressed genes including cell cycle inhibitors. The goal of this study is to better understand the VPA-induced growth inhibition in vivo, by studying expression of markers for various cellular pathways in tissue microarrays (TMA) generated from numerous human Prostate Cancer (PCa) cell xenografts in animals treated chronically with VPA. METHODS For in vitro experiments LNCap and C4-2 cell lines were treated with 0, 0.6, and 1.2 mM VPA for 14 days. At the end of treatment cells were harvested. For in vivo models, nude mice were injected with 1 x 106 cells (LNCap, C4-2 and DU-145) subcutaneously. Experimental animals received 0.4% VPA in drinking water for 35 days. TMA were generated using cell pellets and portions of excised xenografts. Immunohistochemistry staining for acetylated histone H3, cell cycle markers (p21, cyclin D1, p27), Cytokeration 18 (CK18), Androgen receptor (AR), proliferation marker (Ki-67) and CD34 antigen were performed on sections cut from the TMA blocks. Apoptotic cells were identified by TUNEL staining. Induction of acetylated H3 was found, confirming VPA mediated inhibition of histone deacytelase activity. RESULTS VPA treatment causes cell cycle arrest in PCa cells in vivo, as determined by increase in p21 and p27 expression and decrease in cyclinD1 expression. Increased expression of differentiation marker CK18 was also seen in VPA treated xenografts. LNCaP xenografts in treated animals had reduced AR expression when compared to controls. No change in AR expression was found in C4-2 xenografts. While Ki-67 was decreased in LNCaP and C4-2 cell lines treated with VPA in vitro, no reduction in expression was observed in xenografts. DU-145 xenografts, in contrast, demonstrated decreased Ki-67 expression. The TUNEL assay revealed an increase in apoptosis in AR expressing xenografts of LNCaP and C4-2 after VPA treatment. At the same time an anti-angiogenic effect was observed in these xenografts after chronic VPA treatment. CONCLUSIONS Taken together, VPA inhibits tumor growth by multiple mechanisms including cell cycle arrest, induction of differentiation and inhibition of growth of tumor vasculature. While decrease in proliferation was observed in vitro, apoptosis was the primary cause of diminished tumor growth in vivo. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e163 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Abhinav Sidana Cincinnati, OH More articles by this author Muwen Wang Jinan, China, People's Republic of More articles by this author Shabana Shabbeer Baltimore, MD More articles by this author Wasim H. Chowdhury Baltimore, MD More articles by this author George Netto Baltimore, MD More articles by this author Shawn E. Lupold Baltimore, MD More articles by this author Michael Carducci Baltimore, MD More articles by this author Ronald Rodriguez Baltimore, MD More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...