Differential effects of naturally occurring and synthetic organoselenium compounds on biomarkers in androgen responsive and androgen independent human prostate carcinoma cells

Abstract

Epidemiological studies and clinical trials show that selenium supplementation results in reduction of prostate cancer incidence; however, the form of selenium and mechanisms underlying protection remain largely unknown. Toward this end, we compared the effects of naturally occurring selenomethionine (SM) and Semethylselenocysteine (MSC) and synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) and p-xylylbis(methylselenide) p-XMS) organoselenium compounds in androgen responsive (AR) LNCaP and its androgen independent clone (AI) LNCaP C4-2 human prostate carcinoma cells on cell growth, secretion of prostate specific antigen (PSA), intracellular redox status and genomic profiles with emphasis on identifying redox sensitive genes. Both p-XSC and p-XMS reduced cell number and total protein concentration compared to control-treated AR and AI cells, while SM and MSC exhibited no effect on growth of AR and AI cells. SM, p-XSC and p-XMS but not MSC inhibited levels of secreted PSA in AR cells. SM, MSC and p-XMS increased glutathione (GSH) levels in AI LNCaP cells. By contrast, in both cell types, only p-XSC significantly decreased GSH concentrations to <50% of control suggesting either an increase in intracellular oxidative stress or a change in GSH/GSSG ratio. On the basis of RT-PCR analysis, SM and p-XSC increased p53 gene expression by 2-fold in AR cells but not in AI cells and only SM enhanced epidermal growth factor receptor in AR cells. Depending on the structure, organoselenium compounds exhibit differential effects on growth, PSA secretion, oxidative stress and selective gene responses in human prostate cancer cells and suggest the potential of developing novel organoselenium compounds as chemopreventive agents in models of human prostate cancer. ' 2006 Wiley-Liss, Inc.Key words: selenomethionine; Se-methylselenocysteine; 1,4-phenylenebis (methylene)selenocyanate; p-xylylbis(methylselenide); prostate specific antigen; prostate cancer; chemoprevention; glutathione Epidemiological studies, clinical intervention trials and preclinical models have provided evidence for a protective role of organoselenium compounds against development of human cancers, including prostate cancer. [1][2][3][4][5][6][7] Although the anticancer mechanism(s) of selenium-enriched supplements have not been clearly defined, the dramatic outcome of Clark's trial prompted additional clinical trials: Prevention of Cancer by Intervention with Selenium (PRECISE), in 3 European countries, SELECT in the United States, and the Australian Prostate Cancer Prevention Trial Using Selenium (APPOSE) trial. [8][9][10] On the basis of available knowledge, there are compelling viewpoints to investigate systematically how organoselenium compounds modulate the most commonly considered risk factors in the development of prostate cancer not only in cancer patients or in high risk populations but more importantly for chemopreventive measures in healthy males as intended in the SELECT trial. 11Numerous studies strongly support the feasibility of using organ...

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“…MeSeCys, SeMet,). One compound does not described in the above sections is p-xylylbis(methylselenide) (p-XMS) (Figure 6), a organoselenium compound that modifies the growth, secretion of PSA and the intracellular redox status and genomic profiles (Pinto et al, 2007). Too, the selenide function is present linked to nucleosides.…”