Data from Valproic acid causes dose- and time-dependent changes in nuclear structure in prostate cancer cells <i>in vitro</i> and <i>in vivo</i>

Abstract

<div>Abstract<p>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. <i>In vitro</i> 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. <i>In vivo</i> 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 <i>in vitro</i> and <i>in vivo.</i> 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 <i>in vitro</i> and <i>in vivo</i>. Also, VPA treatment caused significant nuclear alterations in normal drug-filtering organs (liver and kidney tissue). <i>In vitro</i> and <i>in vivo</i> 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. [Mol Cancer Ther 2009;8(4):802–8]</p></div>