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，目前还没有有效的治疗策略，表明需要有效的化学预防药物。我们实验室的初步研究表明，无毒的非处方药Nexrutle(TM)(NPS00299)可以抑制雄激素反应性(LNCaP)人前列腺癌细胞和代表不同进展阶段的小鼠前列腺细胞(TRAMP C1和C2；转基因小鼠前列腺癌)的生长。Nexrutin(TM)诱导LNCaP细胞凋亡；降低LNCaP细胞中磷酸化Akt、PDK-1(使Akt在Thr 308上磷酸化)水平；转录因子NF-kappaB的p65组分。此外，在Nexrutle(TM)治疗后，LNCaP细胞中COX-2水平变得不可检测到。 这项试验性建议的目的是在临床前评估Nexrutle(TM)作为一种有效的前列腺癌化学预防药物在TRAMP模型中的使用，并确定其在人前列腺癌细胞和TRAMP小鼠肿瘤中的疗效的分子机制。我们提出了两个具体的目标来研究这一目标：1：利用TRAMP模型确定产生最大活性的奈斯鲁廷(TM)作为预防药物的最有效剂量。我们将评估Nexrutle(TM)对肿瘤的发展、潜伏期、肿瘤的大小和数量以及转移扩散的潜在预防作用。此外，我们将验证在特定目标2中提出的机制研究中确定的凋亡、AKT和NFkappaB信号成分作为Nexrutle(TM)在喂食Nexrutle(TM)后在前列腺癌中的作用的中间标志物；2：探索Akt、NF-kappaB和COX-2在Nexrutle(TM)诱导的细胞凋亡中的作用。我们将进一步研究奈斯鲁廷(TM)诱导人前列腺癌细胞系凋亡的机制，并剖析Akt、NF-kappaB和COX-2在这一过程中的确切作用。目前试点项目的新奇之处在于，它测试了使用廉价可得的膳食补充剂(补充和替代药物)通过调节细胞生存信号通路的关键成分来预防前列腺癌发展的概念。由于在这种临床前模型中，前列腺癌的发展和进展在组织学上类似于人类前列腺癌的发展，因此可以推断这项研究的结果，以进行临床试验，最终将有助于预防人类前列腺癌。

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.