Cancer Chemoprevention by IP6: Efficacy and Mechanism

IP6 的癌症化学预防：功效和机制

• 批准号: 7106165
• 负责人: Rajesh Agarwal
• 金额: $ 26.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7106165
• 关键词: apoptosis; athymic mouse; cell cycle; cell cycle proteins; chemoprevention; death; enzyme inhibitors; human; male; model; neoplasm /cancer; prevention; prostate; prostate neoplasms; protein kinase; tissue /cell culture; xenotransplantation

DESCRIPTION (provided by applicant): The central focus of this grant is to generate critical pre-clinical efficacy and mechanism data with IP6 in various available prostate cancer (PCA) animal models that would set the stage for clinical trials in humans suffering with PCA, which is the most frequently diagnosed invasive malignancy and second most common cause of cancer deaths in males in the United States. Overall, PCA growth and progression involve an aberrant cell cycle progression following gradual accumulation of genetic and epigenetic changes over a period of years. Several mechanisms including a decrease in and/or loss of cyclin-dependent kinase inhibitor (CDKI) function contribute to these events, suggesting that an induction in CDKI level and/or gain in its function is one of the most promising approaches for PCA prevention, growth control and/or therapy. Inositol hexaphosphate (IP6) is a nutrient constituting 6.4% (w/w) or even higher levels in most cereals, legumes, nuts, oil seeds and soybean, and also taken orally as an over-the-counter dietary/nutrient supplement for its several health benefits without any known toxicity. In our recent studies, we found that oral feeding of IP6 to nude mice inhibits the growth of human PCA xenograft without toxicity; completed pilot study in TRAMP model also showed prevention in prostate tumorigenesis by IP6. In PCA cell culture, completed studies by us show that IP6 up- regulates CDKI Kip1/p27 and Cip1/p21 levels together with their increased interaction with CDKs causing inhibition in the kinase activity of CDKs and associated cyclins. These effects of IP6 also caused a G1 arrest, strong inhibition of human and rodent PCA cell growth, and induction of their apoptotic death. No such IP6 effects were observed, however, in non-neoplastic human prostate epithelial cells. Additional studies with siRNA showed that IP6-caused G1 arrest in DU145 cells requires up-regulation of p27 and p21. We also observed that IP6 inhibits PI3K-Akt and NF-KB activation in DU145 cells. Based on these studies, our hypothesis is that p27 and p21 induction is required for cell cycle arrest and in part apoptotic death, together with inhibition of PI3K/Akt/NF-kB activation, by IP6 in its cancer chemopreventive efficacy against PCA. To test this hypothesis, we will: 1) Examine IP6 as a preventive agent in mouse TRAMP and MNU-testosterone rat PCA models; II) Examine efficacy of IP6 in growth control and therapy of PCA using ectopic and orthotopic human prostate carcinoma xenografts in male nude mice; III) Define and characterize in vivo efficacy of IPS on cell cycle regulators in tumor tissues, identify and establish CDKI induction as a molecular target of IP6 action using both cell culture and animal models, and define the mechanism of CDKI induction by IP6 in cell culture; and IV) Define and characterize the in vivo efficacy of IP6 on apoptotic pathways, and identify and establish the role of CDKI, and PI3K-Akt and NF-KB pathways in IPG-induced apoptosis using cell culture systems. Overall, proposed studies would further establish preventive and interventive efficacy of IP6 against PCA and define its molecular mechanisms on cell cycle and apoptosis regulation.

描述（由申请人提供）：这笔资助的核心重点是在各种可用的前列腺癌（PCA）动物模型中使用 IP6 生成关键的临床前疗效和机制数据，这将为患有 PCA 的人类进行临床试验奠定基础，这是美国男性中最常诊断出的侵袭性恶性肿瘤，也是导致男性癌症死亡的第二大常见原因。总体而言，PCA 的生长和进展涉及多年来遗传和表观遗传变化逐渐积累后的异常细胞周期进展。包括细胞周期蛋白依赖性激酶抑制剂 (CDKI) 功能减少和/或丧失在内的多种机制导致了这些事件，表明诱导 CDKI 水平和/或其功能增强是预防 PCA 最有希望的方法之一。生长控制和/或治疗。肌醇六磷酸 (IP6) 是一种营养物质，在大多数谷物、豆类、坚果、油籽和大豆中含量为 6.4% (w/w) 甚至更高，也可作为非处方膳食/营养补充剂口服服用，以提高其营养价值。具有多种健康益处，且没有任何已知的毒性。在我们最近的研究中，我们发现裸鼠口服IP6可以抑制人PCA异种移植物的生长，且无毒性；在 TRAMP 模型中完成的初步研究也表明 IP6 可预防前列腺肿瘤发生。在 PCA 细胞培养中，我们完成的研究表明，IP6 上调 CDKI Kip1/p27 和 Cip1/p21 水平，同时增加它们与 CDK 的相互作用，从而抑制 CDK 和相关细胞周期蛋白的激酶活性。 IP6 的这些作用还导致 G1 期停滞、强烈抑制人类和啮齿动物 PCA 细胞生长，并诱导其凋亡。然而，在非肿瘤性人类前列腺上皮细胞中没有观察到这种 IP6 效应。 siRNA 的其他研究表明，IP6 引起的 DU145 细胞 G1 期停滞需要上调 p27 和 p21。我们还观察到 IP6 抑制 DU145 细胞中 PI3K-Akt 和 NF-KB 的激活。基于这些研究，我们的假设是，p27 和 p21 诱导是细胞周期停滞和部分凋亡死亡所必需的，同时 IP6 抑制 PI3K/Akt/NF-kB 激活，从而发挥其针对 PCA 的癌症化学预防功效。为了检验这一假设，我们将： 1) 在小鼠 TRAMP 和 MNU-睾酮大鼠 PCA 模型中检查 IP6 作为预防剂的作用； II) 使用雄性裸鼠中的异位和原位人前列腺癌异种移植物检查 IP6 在生长控制和 PCA 治疗中的功效； III) 定义和表征 IPS 对肿瘤组织中细胞周期调节因子的体内功效，使用细胞培养和动物模型识别和建立 CDKI 诱导作为 IP6 作用的分子靶标，并定义细胞培养中 IP6 诱导 CDKI 的机制; IV) 定义和表征 IP6 对细胞凋亡途径的体内功效，并使用细胞培养系统识别和确定 CDKI、PI3K-Akt 和 NF-KB 途径在 IPG 诱导的细胞凋亡中的作用。总体而言，拟议的研究将进一步确定 IP6 对 PCA 的预防和干预功效，并明确其对细胞周期和凋亡调节的分子机制。