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）是辣椒属红辣椒的天然产物，已知其在各种癌症模型中诱导细胞凋亡并抑制细胞生长。辣椒素的化学预防机制是细胞特异性的，其功效取决于细胞或组织环境。非甾体抗炎药激活基因-1（NAG-1）是一种在结直肠癌中具有促凋亡和抗肿瘤特性的细胞因子。NAG-1表达与息肉和肿瘤的发生呈负相关，支持NAG-1是化学预防的有希望的分子靶点。我们的初步数据表明，辣椒素导致抑制细胞生长，上调NAG-1和下调细胞周期蛋白D1在人类结直肠癌细胞。在具体的目标1中，我们将通过在体外研究中表征辣椒素如何上调NAG-1和下调细胞周期蛋白D1来研究辣椒素抗肿瘤作用的分子机制。我们将重点研究PKC、GSK 3 <$和C/EBP <$介导辣椒素对NAG-1反式激活的刺激作用。此外，辣椒素对细胞周期蛋白D1和<$-连环蛋白信号传导的抑制将在转录和翻译后水平上确定，重点是<$-连环蛋白的降解和易位，或与E-钙粘蛋白的相互作用。我们期望在体外研究将为我们提供一个新的抗肿瘤途径的辣椒素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NAG-1激活和抑制结直肠癌细胞生长方面具有协同活性。我们将使用结直肠肿瘤模型研究辣椒素单独或与DIM组合对结直肠癌发展的影响，其中[将用辣椒素、DIM或辣椒素+ DIM对野生型或NAG-1敲除小鼠处理氧化偶氮甲烷4周]。在用辣椒素或DIM处理的小鼠中，预期异常隐蔽病灶（ACF）的显著减少，并且在辣椒素+ DIM处理的小鼠中，预期ACF形成的减少比在单独用辣椒素或DIM处理的小鼠中更大。[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中的相加或协同作用。

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.