Pure Flavonolignans from S. marianum in Prostate Cancer

来自 S. marianum 的纯黄酮木脂素在前列腺癌中的应用

• 批准号: 7022926
• 负责人: David J Kroll
• 金额: $ 38.39万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-08 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022926
• 关键词: DNA gyrase; antineoplastics; athymic mouse; bioassay; biological products; biological signal transduction; cancer prevention; cell growth regulation; chemical structure function; chemical synthesis; chemoprevention; drug screening /evaluation; flavonoids; high performance liquid chromatography; insulinlike growth factor; metastasis; neoplastic cell; plant extracts; prostate neoplasms; stereoisomer; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Extracts of milk thistle (Silybum marianum) have been used since antiquity for a number of disorders and have most recently been investigated for utility in hepatic disorders of viral and chemical origin, dyslipidemia, and cancer. Milk thistle extracts, often referred to interchangably as silymarin or silibinin, contain a number of flavonoid and flavonolignan compounds that are responsible for their in vitro and in vivo biological effects. However, studies to ascribe particular biological actions to specific milk thistle components have been few in number due both to the complex stereochemistry of the naturally-occurring compounds and the considerable challenges in isolating these compounds in sufficient quantities. The RTI Natural Products Laboratory has recently succeeded in identifying and isolating from commercially-available silymarin the individual stereoand regio-isomers of milk thistle flavonolignans. These compounds, referred to as silybin A, silybin B, isosilybin A, and isosilybin B, are now available for the first time for characterization of their individual biological activities and, specifically, the determination of their relative contribution to the substantial activity of silibinin and silymarin observed previously in pre-clinical models of human prostate cancer. To do so, the group has established a collaboration with the laboratory of Dr. Rajesh Agarwal at the University of Colorado, the international leader in the demonstrating the efficacy of milk thistle extracts in skin and prostate cancer models and the biochemical mechanisms underlying these responses. This collaborative research group proposes to test the HYPOTHESIS that individual flavonolignan isomers possess distinct biological activities that account for the collective anti-cancer action previously observed for the naturally occurring milk thistle extract mixtures, silibinin and silymarin. Specifically, the group proposes 1) to conduct and optimize the semi-synthesis of the 4 milk thistle flavonolignans in order to isolate each in the larger quantities required for all in vitro and in vivo studies, 2) to investigate the antitumor activity of each individual flavonolignan relative to silibinin and silymarin in DU145 hormone-refractory, metastatic human prostate cancer in immunocompromised mice, 3) to determine the specific biological actions of each flavonolignan on in vitro endpoints of mitogenic cellular signaling and cell cycle progression, and 4) to determine the specific biological actions of each flavonolignan on a) genetic elements in the IGFBP-3 and topoisomerase II gene promoters and b) newly described causative/prognostic factors in human prostate cancer (CXCR4, EZH2, and AMACR). Taken together, these studies are anticipated to advance our biochemical understanding of a highly non-toxic prostate cancer prevention and treatment intervention with the possibility of identifying more efficacious and/or bioavailable combinations of compounds than those occurring naturally.

描述（由申请人提供）：水飞蓟（Silybum marianum）提取物自古以来就被用于治疗多种疾病，并且最近被研究用于治疗病毒和化学来源的肝脏疾病、血脂异常和癌症。水飞蓟提取物通常可互换地称为水飞蓟素或水飞蓟宾，含有许多类黄酮和黄酮木脂素化合物，这些化合物具有其体外和体内生物效应。然而，由于天然存在的化合物的复杂立体化学以及分离足够数量的这些化合物的巨大挑战，将特定的生物作用归因于特定的水飞蓟成分的研究数量很少。 RTI 天然产品实验室最近成功地从市售水飞蓟素中鉴定并分离出水飞蓟黄酮木脂素的单独立体异构体和区域异构体。这些化合物被称为水飞蓟宾 A、水飞蓟宾 B、异水飞蓟宾 A 和异水飞蓟宾 B，现在首次可用于表征其各自的生物活性，特别是确定它们对水飞蓟宾和水飞蓟宾的实质活性的相对贡献。先前在人类前列腺癌的临床前模型中观察到水飞蓟素。为此，该小组与科罗拉多大学 Rajesh Agarwal 博士的实验室建立了合作，该实验室在证明水飞蓟提取物在皮肤癌和前列腺癌模型中的功效以及这些反应背后的生化机制方面处于国际领先地位。该合作研究小组提议测试以下假设：单个黄酮木脂素异构体具有独特的生物活性，这些生物活性解释了先前观察到的天然存在的水飞蓟提取物混合物、水飞蓟宾和水飞蓟素的集体抗癌作用。具体来说，该小组建议 1) 进行和优化 4 种水飞蓟黄酮木脂素的半合成，以便分离出所有体外和体内研究所需的大量的每种水飞蓟黄酮木脂素，2) 研究每种水飞蓟黄酮木脂素的抗肿瘤活性黄酮木脂素相对于水飞蓟宾和水飞蓟素在免疫功能低下小鼠的 DU145 激素难治性转移性人类前列腺癌中的作用，3) 确定具体的生物作用每种黄酮木脂素对有丝分裂细胞信号传导和细胞周期进程的体外终点的影响，以及 4) 确定每种黄酮木脂素对 a) IGFBP-3 和拓扑异构酶 II 基因启动子中的遗传元件和 b) 新描述的致病/的特定生物作用人类前列腺癌的预后因素（CXCR4、EZH2 和 AMACR）。总而言之，这些研究预计将增进我们对高度无毒的前列腺癌预防和治疗干预措施的生化理解，并有可能鉴定出比天然存在的化合物更有效和/或生物利用度更高的化合物组合。