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The development and progression of cardiac hypertrophy often leads to heart failure and death, and important modulators of hypertrophy include the histone deacetylase proteins (HDACs). Estrogen inhibits cardiac hypertrophy and progression in animal models and humans. We therefore investigated the influence of 17-β-estradiol on the production, localization, and functions of prohypertrophic (class I) and antihypertrophic (class II) HDACs in cultured neonatal rat cardiomyocytes. 17-β-Estradiol or estrogen receptor β agonists dipropylnitrile and β-LGND2 comparably suppressed angiotensin II-induced HDAC2 (class I) production, HDAC-activating phosphorylation, and the resulting prohypertrophic mRNA expression. In contrast, estrogenic compounds derepressed the opposite effects of angiotensin II on the same parameters for HDAC4 and 5 (class II), resulting in retention of these deacetylases in the nucleus to inhibit hypertrophic gene expression. Key aspects were confirmed in vivo from the hearts of wild-type but not estrogen receptor β (ERβ) gene-deleted mice administered angiotensin II and estrogenic compounds. Our results identify a novel dual regulation of cardiomyocyte HDACs, shown here for the antihypertrophic sex steroid acting at ERβ. This mechanism potentially supports using ERβ agonists as HDAC modulators to treat cardiac disease.

Prostate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC., Introduction Prostate secretory epithelial cells and neoplastic derivatives are dependent on the androgen receptor (AR) to regulate differentiation, metabolism, growth, and survival (1-3). Currently, inhibition of AR signaling using androgen [...]

To predict the optimal time for surgery after antibody administration, the population pharmacokinetics of [.sup.125.I]-HuCC49ΔCH2 and [.sup.125.I]-CC49 were characterized in 55 patients with colorectal cancers. A 2-compartment linear model was [...]

A review on well-characterized androgen receptor (AR) ligands that bind to the AR with high affinity and discussion regarding the biology, metabolism, and structure-activity relationships for therapeutic and emerging classes of AR ligands is presented. Novel nonsteroidal pharmacophores is summarized with discussion of the emerging structure-activity relationships and examples of their tissue selectivity included.

Despite widespread use in pharmacokinetic, drug metabolism, and pesticide residue studies, little is known about the factors governing response during reversed-phase liquid chromatography coupled with negative-ion electrospray ionization (ES[I.sup.-]) mass spectrometry. We examined the effects of various mobile-phase modifiers on the ES[I.sup.-] response of four selective androgen receptor modulators using a postcolumn infusion system. Acetic, propionic, and butyric acid improved the ES[I.sup.-] responses of analytes to varying extents at low concentrations. Formic acid suppressed ionization, as did neutral salts (ammonium formate, ammonium acetate) and bases (ammonium hydroxide, triethylamine) under most conditions. Two modifiers (2,2,2-trifluoroethanol, formaldehyde) that produce anions with high gas-phase proton affinity increased ES[I.sup.-] responses. However, the concentrations of these modifiers required to enhance ES[I.sup.-] response were higher than that of acidic modifiers, which is a phenomenon likely related to their low p[K.sub.a] values. 2,2,2-Trifluoroethanol increased response of more hydrophobic compounds but decreased response of a more hydrophilic compound. Formaldehyde improved response of all the compounds, especially the hydrophilic compound with lower surface activity. In summary, these results suggest that an ideal ES[I.sup.-] modifier should provide cations that can be easily electrochemically reduced and produce anions with small molecular volume and high gas-phase proton affinity.