Nexrutine, a herbal extract and prostate cancer

描述（由申请人提供）：前列腺癌（PCA）是一个主要的健康问题，目前没有有效的策略可用于其管理，表明需要有效的化学预防剂。我们实验室的初步研究表明，Nexrutine（TM）（NPS 00299），一种非处方的无毒抗炎剂，抑制雄激素反应性（LNCaP）人前列腺癌细胞和小鼠前列腺细胞（TRAMP C1和C2;小鼠前列腺的转基因腺癌）的生长，代表不同的进展阶段。用Nexrutine（TM）处理LNCaP细胞诱导细胞凋亡;降低磷酸化Akt、PDK-1（磷酸化Thr 308上的Akt）的水平; LNCaP细胞中转录因子NF-κ B的p65组分。此外，在Nexrutine（TM）处理后，LNCaP细胞中的考克斯-2水平变得不可检测。 该试验性提案的目的是在临床前评估Nexrutine（TM）在TRAMP模型中作为有效的前列腺癌化学预防剂的用途，并确定其使用人前列腺癌细胞以及来自TRAMP小鼠的肿瘤的功效的分子机制。我们提出了两个具体的目标来研究这一目标：1：确定最有效的剂量Nexrutine（TM），产生最大的活动，其作为一种预防剂使用TRAMP模型。我们将评估Nexrutine（TM）对肿瘤发展、潜伏期、肿瘤大小和数量以及转移扩散的潜在预防作用。此外，我们将验证从特定目标2中提出的机制研究中鉴定的凋亡、Akt和NF κ B信号传导组分作为Nexrutine（TM）在前列腺肿瘤中喂养后Nexrutine（TM）作用的中间标记物的用途; 2：探索Akt、NF-κ B和考克斯-2在介导Nexrutine（TM）诱导的凋亡中的作用。我们将进一步研究Nexrutine（TM）诱导人前列腺癌细胞系凋亡的机制，并分析Akt和NF-κ B和考克斯-2在此过程中的确切作用。目前试点项目的新奇在于，它测试了使用廉价膳食补充剂（补充和替代药物）通过调节细胞存活信号通路的关键成分来预防前列腺癌发展的概念。由于PCA在该临床前模型中的发展和进展在组织学上类似于人类PCA的发展，因此从该研究中获得的结果可以外推到进行最终可用于预防人类前列腺癌的临床试验。

DESCRIPTION (provided by applicant): Prostate cancer (PCA) is a major health problem and currently there are no effective strategies available for its management indicating the need for effective chemopreventive agents. Preliminary studies from our laboratory indicate that Nexrutine(TM) (NPS00299), a non-toxic over the counter anti-inflammatory agent inhibits the growth of androgen-responsive (LNCaP) human prostate cancer cells and mouse prostate cells (TRAMP C1 and C2; transgenic adenocarcinoma of mouse prostate) representing different stages of progression. Treatment of LNCaP cells with Nexrutine(TM) induced apoptosis; reduced the levels of phosphorylated Akt, PDK-1 (that phosphorylates Akt on Thr 308); p65 component of transcription factor NF-kappaB in LNCaP cells. Further, Cox-2 levels became undetectable in LNCaP cells following Nexrutine(TM) treatment. The objective of this pilot proposal is to assess Nexrutine(TM) preclinically for its use as a potent prostate cancer chemopreventive agent in the TRAMP model and to determine the molecular mechanism that underlies its efficacy using human prostate cancer cells as well as in tumors from TRAMP mice. We have proposed two specific aims to investigate this objective; 1: Identify the most effective dose of Nexrutine(TM) that produces maximal activity for its use as a preventive agent using TRAMP model. We will assess the potential preventive effects of Nexrutine(TM) on development of tumors, latency period, size and number of tumors and metastatic spread. In addition we will validate the use of apoptotic, Akt and NFkappaB signaling components identified from mechanistic studies proposed in Specific aim 2 as intermediate markers of Nexrutine(TM) 's action in prostate tumors following feeding with Nexrutine(TM); 2: Explore the role of Akt, NF-kappaB and Cox-2 in mediating Nexrutine(TM)-induced apoptosis. We will further examine the mechanism of Nexrutine(TM) -induced apoptosis in human prostate cancer cell lines and dissect the precise role of Akt and NF-kappaB and Cox-2 in this process. The novelty of the current pilot project is that it tests the concept of the use of a cheaply available dietary supplement (complementary and alternate medicine) in preventing the development of prostate cancer through modulation of key components of the cell survival signaling pathway. Since the development and progression of PCA in this pre-clinical model histologically resembles human PCA development, the results obtained from this study can be extrapolated to conduct clinical trials that will eventually be useful for preventing human prostate cancer.