Valproic acid causes dose- and time-dependent changes in nuclear structure in prostate cancer cells in vitro and in vivo.
Histone deacetylase inhibitors such as valproic acid (VPA) are promising anticancer agents that change the acetylation status of histones and loosen the chromatin structure. We assessed nuclear structure changes induced by VPA in prostate cancer LNCaP, CWR22R, DU145, and PC3 cell lines and xenografts and their potential use as a biomarker of treatment. In vitro tissue microarrays consisted of prostate cancer cell lines treated for 3, 7, or 14 days with 0, 0.6, or 1.2 mmol/L VPA. In vivo tissue microarrays consisted of cores from prostate cancer xenografts from nude mice treated for 30 days with 0.2% or 0.4% VPA in drinking water. Digital images of at least 200 Feulgen DNA-stained nuclei were captured using the Nikon CoolScope and nuclear alterations were measured. With a set of seven most frequently significant nuclear alterations (determined by univariate logistic regression analysis), control and VPA treatment nuclei were compared in vitro and in vivo. Depending on the cell line, area under the curve-receiver operating characteristics ranged between 0.6 and 0.9 and were dose- and time-dependent both in vitro and in vivo. Also, VPA treatment caused significant nuclear alterations in normal drug-filtering organs (liver and kidney tissue). In vitro and in vivo VPA treatment of prostate cancer cell lines results in significant dose- and time-dependent changes in nuclear structure. Further, VPA induces nuclear structural changes in normal liver and kidney tissue, which likely reflects a natural physiologic response. Therefore, nuclear structural alterations may serve as a biomarker for histone deacetylase inhibitor treatment.
Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, James Buchanan Brady Urological Institute, School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Madeleine S Q
MS
Kortenhorst
Sumit
S
Isharwal
Paul J
PJ
van Diest
Wasim H
WH
Chowdhury
Cameron
C
Marlow
Michael A
MA
Carducci
Ronald
R
Rodriguez
Robert W
RW
Veltri
D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D014635:Valproic Acid