Mangostin: A Dietary-Based Xanthone For Prostate Cancer Chemoprevention

描述(由申请人提供)： 据估计，2008年将有20多万新的前列腺癌病例被诊断出来，与前列腺癌相关的死亡人数将超过27,000人。包括核因子kappa B、磷酸肌醇3Kinase/Akt信号网络在内的多种信号通路在前列腺癌的持续和增殖过程中发挥着重要作用。因为大多数化疗药物都是以一种特定的蛋白质或途径为靶点设计的，在临床前和临床环境下，它们往往无法抑制前列腺癌的生长。因此，必须确定具有针对多个信号通路的先天能力的新型小分子(例如，饮食制剂)。在过去的几年里，人们越来越认识到，饮食制剂具有一种天生的能力，可以靶向癌症中多个不受调控的途径，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，我们已经确定了一种新型的膳食剂--α-芒果糖素，这是一种存在于山竹果中的非营养和无毒的天然制剂。α-芒果糖属于一类被称为黄原酮的分子，已被证明具有抗氧化和抗炎活性，然而，人们很少关注它在癌症化学预防方面的潜力。根据我们的初步结果，我们发现芒果苷可以显着降低裸鼠的肿瘤负担，可能是通过抑制我们筛选过程中发现的激酶来实现的。为了实现这一目标，我们提出了两个具体目标：(1)确定芒果糖素的口服安全性和耐受性；(2)确定芒果糖素在TRAMP模型中的有效性。我们认为，这项建议包含了一种更传统的药物开发模式，这将对创建关于α-芒果糖治疗前列腺癌的癌症化学预防潜力的初步数据非常有价值。

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.