Despite the large number of promising nutrient-derived agents demonstrating promise as

Despite the large number of promising nutrient-derived agents demonstrating promise as potential chemopreventive agents most have failed to prove effectiveness in clinical trials. a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must be utilized to evaluate effectiveness in these trials. The goal of this paper is to provide a model using a systematic approach for evaluating the safety effectiveness and mechanism of action of a well characterized nutrient-derived agent-isoflavones – in a phase II clinical trial for prostate cancer (CaP) chemoprevention targeting a population of African American (AA) and Caucasian men. Based on our previous observations we hypothesize that the effects of isoflavones on prostate carcinogenesis are mainly mediated through the down regulation of androgen receptor (AR) and AR activity in AA men is higher due to its shorter length of Glutamine repeats in its N-terminus. We thus believe that isoflavones will exert a stronger protective effect for CaP in AA men and cause a higher activation of FOXO factors and their target genes. The aim of the Avasimibe study is to evaluate the comparative effectiveness of the study agent and placebo in addition to a comparison of the effectiveness and safety in African American males in comparison to Caucasian males treated with this agent. research data have regularly demonstrated that genistein modulates cell proliferation [13-17] angiogenesis [18 19 tumor cell invasion and tumor metastasis [13 20 cell routine rules [22] antioxidant [20 23 and induction of apoptotic cell loss of life [24] indicating that purified isoflavones are encouraging chemopreventive real estate agents with several mobile results that are both genomic and non-genomic. Nevertheless to day the molecular mechanism for cancer-preventive effects of isoflavones is poorly understood. Our computational docking and and proteasome activity studies confirmed that indeed the isoflavone genistein similar to EGCG is a proteasome inhibito [25 26 We also found that genistein at 1 μM could inhibit ~30% of the chymotrypsin-like activity of purified 20S proteasome. It has been reported that plasma levels of genistein are in a range of 0.5-2.5 μM and the concentrations of genistein also vary in different tissues and organs. It is therefore possible that a partial inhibition of the proteasome activity by genistein at a physiological concentration might contribute to its reported cancer-preventative effects. Avasimibe Among different soy compounds genistein was the most potent inhibitor of the proteasomal chymotrypsin-like activity which was consistent with the previous reports where it has also been shown that genistein is the most potent soy isoflavone. Inhibition of proteasome activity by genistein in prostate cancer cells (LNCaP) was associated with increased levels of p27Kip1 IκB-α an important inhibitor of the tumor survival factor NFκB Bax and ubiqutinylated proteins accompanied by induction of apoptotic cell death. We also found that genistein was the most potent one among all the tested isoflavones to induce Bax accumulation and PARP cleavage. However daidzein and glycetin in addition to genistein were able to accumulate p27Kip1 protein. These results suggest that accumulation of Bax and IκB-α is associated with apoptosis induction while p27Kip1 accumulation is probably associated with G1 arrest [24]. Although many activities of genistein have been documented in literature the primary molecular target for genistein remains to be identified. In this regard it is important to note that genistein is also considered a phytoestrogen owing to Avasimibe its structural and functional similarity to estrogens. Various studies showed that genistein binds to ERs and displays receptor- and cell-specific agonistic and agonistic activity on Rabbit Polyclonal to MAP2K1 (phospho-Thr386). estrogen receptors ERα and ERβ in ways nearly the same as tamoxifen which really is a selective estrogen receptor modulator (SERM). Therefore it would appear that ERs represent potential major molecular focuses on for genistein. FOXO protein are a category of forkhead transcriptional elements which are seen as a a conserved DNA binding site termed the “Forkhead package” [27]. Mammalian FOXO elements consist of FOXO1 (previously referred to as FKHR) FOXO3A (previously referred to as FKHRL1) FOXO4 (previously referred to as AFX) and FOXO6 [28]. These elements control the manifestation of a number of Avasimibe genes that regulate important cellular procedures (Shape 1) such as for example cell routine apoptosis oxidative tension atrophy energy homeostasis and blood sugar metabolism tumorigenesis.