Mechanisms of Triterpenoids in Prevention of Prostate Cancer

描述（由申请人提供）： 定期使用包括选择性 COX-2 抑制剂在内的非甾体抗炎药 (NSAID) 可降低患前列腺癌的风险。然而，与长期使用COX-2抑制剂相关的显着胃肠道和肾毒性以及心血管事件风险增加破坏了这些药物作为化学预防剂的使用。具有抗炎和抗氧化活性且无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，在传统医学中用作抗菌、抗炎和抗癌剂。最近的研究表明，合成齐墩果烷三萜类化合物：2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic Acid (CDDO) 及其 C-28 甲酯 (CDDO-Me) 和 C-28 咪唑 (CDDO-Im) 是有效的抗炎剂。我们的初步数据表明，合成三萜类化合物强烈抑制前列腺癌细胞系的细胞增殖并诱导细胞凋亡，其效力顺序为CDDO-Me>CDDO-Im>CDDO。此外，CDDO-Me 可抑制抗凋亡 Akt 和 Akt 调节的 NF-:B 和 p-mTOR 促生存信号分子的表达以及体内肿瘤异种移植物的生长。我们假设，CDDO-Me 的早期干预将通过抑制 Akt、NF-:B 和 mTOR 以及这些分子调节的细胞过程（例如细胞增殖、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以及裸鼠原位肿瘤异种移植物的生长。我们将通过执行四个具体目标来检验这一假设。具体目标 1 将检验以下假设：CDDO-Me 的早期干预将阻止 TRAMP 小鼠前列腺癌的发生和/或延缓其进展。具体目标 2 将测试 CDDO-Me 预防前列腺肿瘤发生与抑制 Akt/NF-:B 和 Akt/mTOR 信号通路以及这些分子靶标调节的细胞过程（细胞增殖、凋亡、炎症、转移和血管生成）有关。具体目标3将确定CDDO-Me抑制Akt的机制，具体目标4将确定CDDO-Me在原位异种移植模型中抑制前列腺肿瘤生长的功效和机制。这项研究将为 CDDO-Me 作为人类前列腺癌安全化学预防/治疗剂的功效和作用机制提供重要的临床前信息。公共卫生相关性 由于前列腺癌的发展在很长一段时间内进展缓慢，因此采用无毒草药化合物进行早期干预以预防或减缓前列腺癌的进展是征服这种疾病的一种有前途的方法。我们的建议是研究 CDDO-Me（一种源自天然齐墩果酸的合成三萜类化合物）在 TRAMP 小鼠和肿瘤异种移植模型中预防前列腺癌的功效和作用机制，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.