Combinational anti-cancer effects of capsaicin and 3,3'-diindolylmethane in color

描述(由申请人提供)： 辣椒素(反式-8-甲基-N-香草基-6-壬烯酰胺)是辣椒属植物的天然产物，在多种癌症模型中均可诱导细胞凋亡和抑制细胞生长。辣椒素的化学预防机制是细胞特异性的，其疗效取决于细胞或组织环境。非类固醇抗炎药(NSAID)激活基因-1(NAG-1)是一种与结直肠癌促凋亡和抗肿瘤相关的细胞因子。NAG-1的表达与息肉和肿瘤的发生呈负相关，支持NAG-1是化学预防的一个有前途的分子靶点。我们的初步数据表明，辣椒素可以抑制人结肠癌细胞的生长，上调NAG-1的表达，下调细胞周期蛋白D1的表达。在特定的目标1中，我们将通过体外研究辣椒素上调NAG-1和下调细胞周期蛋白D1的方式来探讨辣椒素抗肿瘤作用的分子机制。我们将重点介绍PKC、GSK3和C/EBP在辣椒素刺激NAG-1反式激活中的作用。此外，辣椒素对细胞周期蛋白D1和连环蛋白信号的抑制将在转录和翻译后水平上确定，重点是连环蛋白的降解和转位，或与E-钙粘附素的相互作用。我们预计，体外研究将为我们提供一种新的抗肿瘤途径，即辣椒素对促凋亡和抗增殖的调节。在我们的初步数据中，我们发现辣椒素与3，3‘-二吲哚甲烷(DIM)在激活NAG-1和抑制结直肠癌细胞生长方面具有协同活性。我们将使用结直肠癌模型[在野生型或NAG-1基因敲除小鼠中用辣椒素、DIM或辣椒素+DIM治疗偶氮甲烷]4周，研究辣椒素单独或与DIM联合应用对结直肠癌发生的影响。预计辣椒素或DIM治疗的小鼠的异常隐匿灶(ACF)将显著减少，辣椒素+DIM治疗的小鼠ACF形成的减少程度预计比单独使用辣椒素或DIM的小鼠更大。[NAG-1基因的敲除有望改善辣椒素/DIM诱导的抗肿瘤活性]。体内研究将揭示辣椒素和DIM在抑制结直肠肿瘤发生方面的相加或协同作用。

DESCRIPTION (provided by applicant): Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a natural product of the Capsicum species of red peppers, is known to induce apoptosis and suppress cell growth in various cancer models. The chemopreventive mechanism of capsaicin is cell specific, and its efficacy is dependent on cell or tissue context. Non-steroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and anti-tumorigenic properties in colorectal cancer. NAG-1 expression is inversely correlated with the occurrence of polyps and tumor, supporting that NAG-1 is a promising molecular target in chemoprevention. Our preliminary data demonstrate that capsaicin leads to suppression of cell growth, up-regulation of NAG-1 and down-regulation of cyclin D1 in human colorectal cancer cells. In specific aim 1, we will investigate the molecular mechanism of capsaicin's anti-tumor effect by characterizing how capsaicin up-regulates NAG-1 and down-regulates cyclin D1 in in vitro studies. We will focus on the roles of PKC, GSK3¿, and C/EBP¿ mediating the stimulatory effects of capsaicin on NAG-1 transactivation. In addition, suppression of cyclin D1 and ¿-catenin signaling by capsaicin will be determined at transcriptional as well as post-translational levels, focusing on ¿-catenin degradation and translocation, or interaction with E-cadherin. We anticipate in vitro studies will provide us a new anti-tumorigenic pathway of pro-apoptotic and anti-proliferative regulation by capsaicin. In our preliminary data, we found that capsaicin had synergistic activity with 3,3'- diindolylmethane (DIM) in NAG-1 activation and suppression of colorectal cancer cell growth. We will investigate the effects of capsaicin alone or in combination with DIM on the development of colorectal cancer using a colorectal tumor model in which [azoxymethane will be treated with capsaicin, DIM, or capsaicin + DIM into wild type or NAG-1 knockout mice] for 4 weeks. Significant reductions in aberrant cryptic foci (ACF) will be expected in mice treated with capsaicin or DIM, and a greater reduction of ACF formation in capsaicin + DIM treated mice is expected than that in mice treated with capsaicin or DIM alone. [Knockout of the NAG-1 gene is expected to ameliorate capsaicin/DIM-induced antitumorigenic activities]. In vivo studies will reveal the additive or synergistic effect of capsaicin and DIM in suppression of colorectal tumorigenesis.