Colon Cancer Inhibition by a Class of PPARgamma Agonists

描述(申请人提供)：结直肠癌是发达国家男性和女性癌症死亡的主要原因，每年有100多万新病例和500,000人死亡。遗传性结直肠癌的易感性只占所有病例的15%-25%，而75%-85%的结肠癌是散发性的，与环境/饮食因素有关。本实验室的研究已经确定了一系列1，1-二(3‘-吲哚)-L-(对取代苯基)甲烷[C-取代二吲哚甲烷(DIMS)]，它们在体内毒性很低，但通过激活过氧化物酶体增殖物激活受体y(PPARy)抑制结肠癌和结肠癌细胞的生长。我们假设PPARy活性的C-取代DIMS代表了一类新的治疗结肠癌的基于机制的药物。目的1将使用一系列包含对苯环和吲哚环取代基的类似物进一步研究依赖PPAR？的反式激活和共激活子招募的激活。这些研究和其他研究将在六个具有明确分子特征的结肠癌细胞株中进行，包括至少两个表达野生型PPARy(HT-29)和K422Q突变体PPARy(HCT-15)的细胞株，它们对其他PPARy激动剂如罗格列酮不敏感。罗格列酮和PPARy活性的C-取代DIMS在结肠癌细胞系中的生长抑制活性的比较将被广泛研究。目的2在初步研究的基础上，重点阐述PPARy活性C-取代DIMS抑制肿瘤细胞生长的机制，这些机制可能与细胞周期基因/蛋白(p21和细胞周期蛋白D1)以及分化标志物如小窝蛋白1和2有关。初步研究将集中在PPARy活性C-取代DIMS诱导小窝蛋白作为通过RNA干扰野生型和PPAR？灭活细胞抑制癌细胞生长的关键途径。目的研究PPARy活性C取代DIMS对结肠癌易感转基因小鼠和裸鼠裸鼠移植瘤生长的抑制作用。这些拟议的研究将为PPARy依赖的结肠癌抑制提供机制上的见解，并为未来的临床研究确定化合物。

DESCRIPTION (provided by applicant): Colorectal cancer is a major cause of cancer deaths in men and women in developed countries, and over a million new cases and 500,000 deaths occur each year. Inherited susceptibility to colorectal cancer only accounts for 15-25% of all cases, whereas, 75-85% of colon cancer is sporadic and associated with environmental/dietary factors. Studies in this laboratory have identified a series of 1,1-bis (3'-indolyl)-l- (p-substituted phenyl) methanes [C-substituted diindolylmethanes (DIMs)], which exhibit low in vivo toxicity but inhibit colon tumor and colon cancer cell growth through activation of peroxisome proliferator-activated receptor y (PPARy). We hypothesize that PPARy-active C-substituted DIMs represent a new class of mechanism-based drugs for treatment of colon cancer. Aim 1 will further investigate activation of PPAR ? -dependent transactivation and coactivator recruitment using a series of analogs containing both p-phenyl and indole ring substituents. These and other studies will be carried out in six colon cancer cell lines with defined molecular features including at least two cell lines which express wild-type PPARy (HT-29) and K422Q mutant PPARy, (HCT-15), which are non-responsive to other PPARy agonists such as rosiglitazone. The comparative growth inhibitory activities of rosiglitazone and PPARy-active C-substituted DIMs in colon cancer cell lines will be extensively investigated. Aim 2 will focus on the mechanisms of growth inhibition by PPARy-active C-substituted DIMs and based on preliminary studies, which appear to be associated with cell cycle genes/proteins (p21 and cyclin D1) and markers of differentiation such as caveolin 1 and 2. Initial studies will focus on the role of caveolin induction by PPARy-active C-substituted DIMs as a critical pathway for inhibition of cancer cell growth using wild-type and PPAR? -inactivated cells through RNA interference. Aim 3 will investigate inhibition of colon tumor growth in transgenic Min mice that are susceptible to colon cancer and athymic nude mouse models bearing colon cancer cells as xenografts and treated with PPARy-active C-substituted DIMs. The proposed studies will provide mechanistic insights on PPARy-dependent inhibition of colon cancer and identify compounds for future clinical studies.