Mechanisms of Triterpenoids in Prevention of Prostate Cancer

三萜类化合物预防前列腺癌的机制

• 批准号: 7524417
• 负责人: SUBHASH C GAUTAM
• 金额: $ 30.09万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524417
• 关键词: 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; Adenocarcinoma; Adverse effects; Androgens; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Antioxidants; Apoptosis; Cardiovascular system; Cell Proliferation; Cell physiology; Chemopreventive Agent; Clinical Trials; Data; Development; Disease; Drug usage; Early Intervention; Epidemiologic Studies; Event; Growth; Human; Imidazole; Inflammation; Intestines; Kidney; LNCaP; Link; Malignant neoplasm of prostate; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Nude Mice; Oleanolic Acid; PC3 cell line; PTGS2 gene; Pharmaceutical Preparations; Pharmacologic Substance; Prevention; Prostate; Prostatic Neoplasms; Reporting; Resistance; Risk; Signal Pathway; Signal Transduction Pathway; Signaling Molecule; Stomach; Testing; Therapeutic Agents; Time; Toxic effect; Traditional Medicine; Transgenic Organisms; Triterpenes; Vascular Endothelial Growth Factors; Xenograft Model; angiogenesis; cardiovascular risk factor; human FRAP1 protein; in vivo; inhibitor/antagonist; mTOR Signaling Pathway; man; methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate; neoplastic cell; oleanane; pre-clinical; prevent; prostate cancer prevention; tumor; tumor xenograft; tumorigenesis; ursolic acid

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.

描述（由申请人提供）： 定期使用非甾体抗炎药（NSAID），包括选择性考克斯-2抑制剂，可降低前列腺癌的风险。然而，长期使用考克斯-2抑制剂会产生显著的胃肠和肾毒性，并增加心血管事件的风险，这削弱了这些药物作为化学预防剂的应用。具有抗炎和抗氧化活性而没有严重副作用的草药为预防前列腺癌提供了这些药物的有吸引力的替代品。油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剂、抗炎剂和抗癌剂。最近的研究表明，合成的齐墩果烷三萜类化合物：2-氰基-3，12-二氧代齐墩果烷-1，9（11）-二烯-28-酸（CDDO）及其C-28甲基酯（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，合成的三萜类化合物强烈抑制前列腺癌细胞系中的细胞增殖并诱导凋亡，效力顺序为CDDO-Me>CDDO-Im>CDDO。此外，CDDO-Me抑制抗凋亡Akt和Akt调节的NF-：B和p-mTOR促存活信号传导分子的表达以及体内肿瘤异种移植物的生长。我们假设用CDDO-Me的早期干预将通过抑制Akt、NF-：B和mTOR以及由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）。我们将通过执行四个具体目标来验证这一假设。具体目标1将检验用CDDO-Me的早期干预将预防TRAMP小鼠中前列腺癌的发展和/或延缓其进展的假设。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信号传导途径以及由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）相关。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抑制原位异种移植模型中前列腺肿瘤生长的功效和机制。这项研究将提供关键的临床前信息的有效性和作用机制的CDDO-Me作为一种安全的化学预防/治疗剂的前列腺癌man. Public健康相关性前列腺癌的发展缓慢，在很长一段时间内，早期干预无毒的草药化合物，以防止或减缓前列腺癌的进展是一个有前途的方法来征服这种疾病。我们的建议是研究CDDO-Me（一种源自天然存在的油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，这将为CDDO-Me预防人类前列腺癌的临床试验提供关键信息。