The prostate cancer blocking potential of the histone deacetylase inhibitor LBH589 is not enhanced by the multi receptor tyrosine kinase inhibitor TKI258.

Pharmacologic options for patients with castration-resistant prostate cancer are limited. It has been suggested that targeting intracellular molecules, which have been altered during neoplastic development, may slow tumor growth. Therefore, the growth-blocking potential of the histone deacetylase-inhibitor LBH589 and the multiple tyrosine kinase-inhibitor TKI258, applied alone or in combination, was investigated in a panel of prostate cancer cell lines. PC-3, DU-145 or LNCaP cells were treated with various concentrations of LBH589 and/or TKI258. Tumor cell growth, cell cycle regulating proteins, HDAC3- and HDAC4-expression and histone H3 and H4 acetylation were then evaluated by MTT assay and Western blotting. LBH589 dose-dependently blocked prostate cancer cell growth. In contrast, TKI258 did not down-regulate tumor cell growth up to a 1,000 nM dosage. LBH589 elevated histone H3 and H4 acetylation. The cell cycle regulators cyclin B, cyclin D1, cdk1 and cdk4 were down-regulated in PC-3, whereas the suppressor proteins p21 and p27 were up-regulated in LNCaP by LBH589. TKI258 up-regulated p27 in PC-3 or p21 in LNCaP and additionally elevated cyclin B, cyclin D1, cdk1 and cdk4 in both cell lines. Presumably, the increase in cyclin and cdk caused by TKI258 counteracts the benefit of p21 or p27 up-regulation, resulting in TKI258 non-responsiveness. The LBH589/TKI258-combination was not superior to the LBH589 single-drug use in terms of growth reduction. Obviously, TKI258 did not enhance the sensitivity of prostate cancer cells towards an HDAC based regimen. Therefore, the LBH589/TKI258-combination probably does not provide an optimum strategy in fighting advanced prostate cancer.

Castrati singers--all for fame.

INTRODUCTION: The phenomenon of castration is very closely associated with the baroque era. In a period that placed emphasis on pure sensual pleasure, castrati singers, with their angelic voices, were a perverted outcome of this ambition. It was the intention that these castrato voices with their supernatural sound would mesmerize audiences. At that time, it could be said that within certain society circles, an addiction to these voices existed. Equally, they were oblivious to the spiritual side of the lives of the castrati. Farinelli, Caffarelli, and Senesino, three of the most famous castrati, were the first musical superstars of the 18th century. Their voices moved decadent audiences to tears and standing ovations. The price for this fame was, however, high. AIM: The aim of this review is to provide an overview of castrati singers, especially in the baroque era, their sexuality and the effects of castration on their physical development. METHODS: A literature search of relevant databases, books, and articles in journals was performed and compared with current data concerning androgen suppression and endocrine aspects of male sexual dysfunction. RESULTS: The effects of castration on physical development were notoriously erratic. Much depended on the timing of the operation: boys pruned before the age of 10 or so very often grew up with feminine features; smooth, hairless bodies, incipient breasts, infantile penis, and often a complete lack of sex drive. CONCLUSION: The peak success of the castrati ended with the end of the 18th century. The last castrato was Alessandro Moreschi, a solo singer in the choir of the Sistine Chapel of the Vatican. Following the ban on castration, Pope Pius X sent him into retirement in 1912, thus putting an end to a very impressive part of the history of music.