Mangostin: A Dietary-Based Xanthone For Prostate Cancer Chemoprevention

Mangostin：一种基于膳食的氧杂蒽酮，用于前列腺癌的化学预防

• 批准号: 7789273
• 负责人: Jeremy James Johnson
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789273
• 关键词: Acute; Androgens; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attention; Back; Biological Assay; CWR22Rv1; Cancer Control; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Clinic; Clinical; Complement; Complex; Cyclin D1; Data; Development; Diagnosis; Diet; Discipline; Dose; Drug Formulations; Drug Kinetics; Elements; Ensure; Epidemiology; Epigallocatechin Gallate; Flavonoids; Food; Foundations; Fruit; Future; Garcinia mangostana; Genistein; Goals; Growth; High Pressure Liquid Chromatography; In Vitro; Inositol; Intervention; K-Series Research Career Programs; LNCaP; Laboratory Study; Light; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Marketing; Maximum Tolerated Dose; Modeling; Mus; NF-kappa B; Nature; Nude Mice; Nutrient; Oral; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Process; Property; Prostate; Proteins; Research; Safety; Screening procedure; Serum; Signal Pathway; Signal Transduction; Translating; Tumor Burden; Tumor Volume; Tumor Weights; Xanthones; Xenograft Model; animal efficacy; base; cancer cell; cancer chemoprevention; cell growth; chemotherapeutic agent; commercialization; cyclin A1; cytotoxicity; design; drug development; in vivo; novel; pre-clinical; programs; prostate cancer prevention; research clinical testing; research study; response; small molecule; trait; translational study; tumor

DESCRIPTION (provided by applicant): In 2008 it is estimated that over 200,000 new cases of prostate cancer will be diagnosed and over 27,000 prostate related cancer deaths will occur. Multiple signaling pathways that include nuclear factor kappa B, Phosphotidyl Inositol 3 Kinase/Akt signaling network as well as others are behaving in a manner that promotes the persistence and proliferation of prostate cancer. Since the majority of chemotherapeutic agents have been designed in such a fashion to target one specific protein or pathway and they will often fail to inhibit the growth of prostate cancer in preclinical and clinical settings. Therefore, it is essential that novel small molecules (e.g. dietary agents) be identified that have an innate ability to target multiple signaling pathways. Over the last several years it is becoming increasingly appreciated that dietary agents have an innate ability to target multiple deregulated pathways in cancer and more importantly may be an effective strategy that can be translated to the clinic. It is on this principle that we have identified a novel dietary agent, alpha-Mangostin, a non- nutrient and non-toxic natural agent present in the Mangosteen fruit (Garcinia mangostana). Alpha- Mangostin belongs to a class of molecules called xanthones that have been shown to display antioxidant and anti-inflammatory activity, however, little attention has been given to its potential for cancer chemoprevention. Based on our preliminary results we have found that Mangostin can significantly reduce the tumor burden in athymic nude mice potentially throught the inhibition of kinases as identified in our screening process. To achieve this goal we are proposing two specific aims: (1) Determine the oral safety and tolerability of Mangostin in (2) Determine the efficacy of Mangostin in the TRAMP model when administered in food pellets. We believe that this proposal incorporates a more traditional drug development model that will be extremely valuable in creating preliminary data about the cancer chemopreventive potential of alpha-Mangostin for prostate cancer.

描述（由申请人提供）： 据估计，2008年将诊断出超过200，000例新的前列腺癌病例，并且将发生超过27，000例前列腺相关癌症死亡。包括核因子κ B、磷脂酰肌醇3激酶/Akt信号网络以及其他的多种信号通路以促进前列腺癌的持续和增殖的方式起作用。由于大多数化学治疗剂已经以靶向一种特定蛋白质或途径的方式设计，因此它们在临床前和临床环境中通常不能抑制前列腺癌的生长。因此，鉴定具有靶向多种信号传导途径的先天能力的新型小分子（例如膳食剂）是至关重要的。在过去的几年里，人们越来越认识到膳食剂具有靶向癌症中多个失调途径的先天能力，更重要的是，它可能是一种可以转化为临床的有效策略。正是基于这一原理，我们已经鉴定了一种新的膳食剂，α-山竹素，一种存在于山竹果实（Garcinia mangostana）中的无营养且无毒的天然剂。α-芒果素属于一类被称为氧杂蒽酮的分子，其已被证明具有抗氧化和抗炎活性，然而，很少有人关注其用于癌症化学预防的潜力。基于我们的初步结果，我们发现Mangostin可以显着降低无胸腺裸鼠的肿瘤负荷，可能与我们筛选过程中鉴定的激酶抑制作用一致。为了实现这一目标，我们提出了两个具体目标：（1）确定Mangostin的口服安全性和耐受性;（2）确定Mangostin在TRAMP模型中以食物颗粒给药时的疗效。我们认为，该提案结合了一种更传统的药物开发模型，这对于创建关于α-Mangostin对前列腺癌的癌症化学预防潜力的初步数据非常有价值。