No abstract

The purpose of this study was to further characterize cell growth-inhibitory effects of a recently identified androgen receptor (AR) signaling inhibitor 6-amino-2-[2-(4-tert-butyl-pnenoxy)-ethylsulfanyl]-1H-pyrimidin-4-one (DL3)5 and antiandrogen bicalutamide (Bic). DL3 was more potent than Bic in induction of G1 arrest and reduction of G1-related cell cycle protein expression in AR-positive LNCaP cells. DL3, but not Bic, moderately inhibited growth of AR-negative PC-3 cells independent of G1 arrest. The data indicated that DL3 inhibit cell growth in both ARdependent and -independent manners and is potentially a potent therapeutic agent for the management of advanced human prostate cancer.

A biosensor is an electronic device that measures biologically important parameters. An example is a sensor that measures the chemicals and materials released during corrosion of a biodegradable magnesium implant that impact surrounding cells, tissues and organs. A responsive biosensor is a biosensor that responds to its own measurements. An example is a sensor that measures the corrosion of an implant and automatically adjusts (slows down or speeds up) the corrosion rate. The University of Cincinnati, the University of Pittsburgh, North Carolina A&T State University, and the Hannover Medical Institute are collaborators in an NSF Engineering Research Center (ERC) for Revolutionizing Metallic Biomaterials (RBM). The center will use responsive sensors in experimental test beds to develop biodegradable magnesium implants. Our goal is to develop biodegradable implants that combine novel bioengineered materials based on magnesium alloys, miniature sensor devices that monitor and control the corrosion, and coatings that slow corrosion and release biological factors and drugs that will promote healing in surrounding tissues. Responsive biosensors will monitor what is happening at the interface between the implant and tissue to ensure that the implant is effective, biosafe, and provides appropriate strength while degrading. Corrosion behavior is a critical factor in the design of the implant. The corrosion behavior of implants will be studied using biosensors and through mathematical modeling. Design guidelines will be developed to predict the degradation rate of implants, and to predict and further study toxicity arising from corrosion products (i.e., Mg ion concentrations, pH levels, and hydrogen gas evolution). Knowing the corrosion rate will allow estimations to be made of implant strength and toxicity risk throughout the degradation process.

Abstract. Heat shock protein (hsp) 70-1 (hsp70-1) is overexpressed in human prostate cancer cells and may play important roles in prostate cancer resistance to conventional therapies. The purpose of this study was to investigate whether androgen receptor (AR) and its signaling regulate hsp70-1 expression. Several lines of AR-positive (LNCaP, LAPC-4, and 22Rv1) and -negative (PC-3, DU145, WPE1-NB14 and WPE1-NB-26) human prostatic cells were used in the study. Dihydrotestosterone (DHT) enhanced hsp70-1 expression in LNCaP cells. Expression of hsp70-1 in LNCaP cells was downregulated by the anti-androgens bicalutamide (Bic), and flutamide (Flut), and a newly identified AR signaling antagonist DL3. The downregulation of hsp70-1 by DL3 was also observed in LAPC-4 and 22Rv1 cells, but not in the four lines of AR-negative cells examined. Expression of hsp70-1 was also reduced by DL3 in PC-3 cells engineered with AR. On the other hand, knocking down AR in LNCaP cells by siRNA moderately reduced hsp70-1 level and abolished effects of DL3 on hsp70-1 expression. DL3 reduced hsp70-1 mRNA synthesis in cells and its in vitro gene transcription but did not significantly alter the stabilities of hsp70-1 mRNA and protein. Chromatin-immunoprecipitation (ChIP) assay showed that AR bound to the promoter region of HSPA1B gene, which was reduced in cells treated with DL3 or Bic. These data suggest that AR and its signaling regulate hsp70-1 expression in prostate cancer cells and that HSPA1B could be an AR target gene.