Mechanisms of Triterpenoids in Prevention of Prostate Cancer

描述(由申请人提供)： 定期使用非类固醇抗炎药(NSAIDs)，包括选择性的COX-2抑制剂，可以降低前列腺癌的风险。然而，与长期使用COX-2抑制剂相关的显著的胃肠和肾脏毒性，以及心血管事件风险的增加，削弱了这些药物作为化学预防药物的使用。具有抗炎和抗氧化活性且没有严重副作用的草药为预防前列腺癌提供了一种有吸引力的替代药物。齐墩果酸和熊果酸是天然存在的三萜类化合物，在传统医学中被用作抗菌、抗炎和抗癌药物。近年来的研究表明，合成齐墩果烷三萜类化合物2-氰基-3，12-二氧代-1，9(11)-二烯-28-油酸(CDDO)及其C-28甲酯(CDDO-Me)和C-28咪唑(CDDO-Im)是有效的抗炎药。我们的初步数据表明，合成的三萜类化合物对前列腺癌细胞株具有强烈的抑制细胞增殖和诱导细胞凋亡的作用，其作用强度顺序为CDDO-Me&GT；CDDO-Im&gt；CDDO。此外，CDDO-Me还可抑制抗细胞凋亡的Akt和Akt调节的促生存信号分子Nf-：B和p-mTor的表达，抑制体内移植瘤的生长。我们推测，CDDO-Me早期干预将通过抑制Akt、NF-：B和mTOR以及这些分子调控的细胞过程(如细胞增殖、凋亡、炎症、血管生成和转移)来预防或延缓转基因小鼠前列腺癌(TRAMP)模型中前列腺癌的发展和裸鼠原位肿瘤移植瘤的生长。我们将通过实现四个具体目标来检验这一假设。特定目标1将验证这样的假设，即早期使用CDDO-Me干预将防止和/或延缓TRAMP小鼠前列腺癌的发展和/或进展。特异性靶点2将测试CDDO-Me预防前列腺癌的发生与抑制Akt/NF-：B和Akt/mTor信号通路以及由这些分子靶点调控的细胞过程(细胞增殖、凋亡、炎症、转移和血管生成)有关。特异靶3将确定CDDO-Me抑制Akt的机制，特异靶4将确定CDDO-Me在原位异种移植模型中抑制前列腺癌生长的疗效和机制。这项研究将为CDDO-Me作为一种安全的前列腺癌化学预防/治疗药物的有效性和作用机制提供关键的临床前信息。公共卫生保健相关性由于前列腺癌的发展在很长一段时间内进展缓慢，早期干预无毒草药化合物以预防或减缓前列腺癌的进展是征服这种疾病的一种有希望的方法。CDDO-Me是一种从天然齐墩果酸中提取的合成三萜类化合物，我们的研究将为CDDO-Me预防人类前列腺癌的临床试验提供关键信息。

DESCRIPTION (provided by applicant): Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) including selective COX-2 inhibitors reduces the risk of prostate cancer. However, significant gastro-intestinal and renal toxicity, and increased risk of cardiovascular events associated with long-term use of COX-2 inhibitors undermine the use of these drugs as chemopreventive agents. Herbal remedies with anti-inflammatory and antioxidant activity without serious side effects provide an attractive alternative to these pharmaceuticals for prevention of prostate cancer. Oleanolic acid and ursolic acid are naturally occurring triterpenoids that have been used in traditional medicine as antibacterial, anti-inflammatory, and anti-cancer agents. Recent studies have shown that synthetic oleanane triterpenoids: 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO- Me) and C-28 imidazole (CDDO-Im) are potent anti-inflammatory agents. Our preliminary data demonstrate that synthetic triterpenoids strongly inhibit cell proliferation and induce apoptosis in prostate cancer cell lines in potency order of CDDO-Me>CDDO-Im>CDDO. Furthermore, CDDO-Me inhibits the expression of antiapoptotic Akt and Akt-regulated NF-:B and p-mTOR pro-survival signaling molecules and growth of tumor xenografts in vivo. We hypothesize that early intervention with CDDO-Me will prevent or delay the development of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) model and growth of orthotopic tumor xenografts in nude mice by inhibiting Akt, NF-:B and mTOR, and cellular processes regulated by these molecules (e.g., cell proliferation, apoptosis, inflammation, angiogenesis and metastasis). We will test this hypothesis by performing four specific aims. Specific Aim 1 will test the hypothesis that early intervention with CDDO-Me will prevent the development and/or retard the progression of prostate cancer in TRAMP mice. Specific Aim 2 will test that prevention of prostate tumorigenesis by CDDO-Me is linked to the inhibition of Akt/NF-:B and Akt/mTOR signaling pathways and cellular processes (cell proliferation, apoptosis, inflammation, metastasis, and angiogenesis) regulated by these molecular targets. Specific Aim 3 will determine the mechanism by which CDDO-Me inhibits Akt, and Specific Aim 4 will determine the efficacy and the mechanism by which CDDO-Me inhibits the growth of prostate tumor in an orthotopic xenograft model. This study will provide critical preclinical information on the efficacy and mechanism of action of CDDO-Me as a safe chemopreventive/therapeutic agent for prostate cancer in man. PUBLIC HELATH RELEVANCE Because the development of prostate cancer progresses slowly over a long period of time, early intervention with non-toxic herbal compounds to prevent or slow down the progression of prostate cancer is a promising approach to conquer this disease. Our proposal to investigate the efficacy and the mechanism of action of CDDO-Me, a synthetic triterpenoid derived from naturally occurring oleanolic acid, in prevention of prostate cancer in TRAMP mouse and tumor xenograft models will provide critical information for clinical trials of CDDO-Me to prevent prostate cancer in man.