Lupeol, A Novel Fuit and Vegetable Based Triterpene for Prostate Cancer

描述(由申请人提供)： 据估计，2006年仅在美国就将诊断出234,460例新的前列腺癌病例，预计约有27,350例与前列腺癌有关的死亡。分离的癌细胞的持久性(即使在手术和雄激素消融治疗后)、它们的增殖、雄激素非依赖性和对远处部位的侵袭是导致人类前列腺癌患者死亡的主要原因。多种蛋白质或分子通路，包括β-连环素、核因子-kappaB和磷脂酰肌醇-3-激酶/Akt信号网络，其水平和功能的异常与前列腺癌细胞的雄激素非依赖性、增殖、侵袭和化疗耐药有关。由于大多数化疗药物通常针对特定的蛋白质或分子途径，因此在临床前和临床环境下，它们往往无法抑制晚期前列腺癌的生长。因此，重要的是要找到能够靶向多个分子途径的新型药物。人们越来越认识到，通过饮食为基础的天然药物进行化学预防可能是预防和治疗人类前列腺癌的有效方法。根据我们已发表的研究和初步数据，我们认为羽扇豆醇是一种存在于草莓、葡萄、芒果、无花果、橄榄和蔬菜中的无营养、无毒的天然制剂，可能是一种理想的化学预防和治疗药物，具有多个分子途径的作用能力。我们推测羽扇豆醇可能通过调节β-连环蛋白、核因子-kappaB和磷脂酰肌醇-3-激酶/Akt信号网络，在杀伤高侵袭性和耐药的前列腺癌细胞的同时，抑制其增殖和侵袭。必须强调的是，与NCI目前的意见一致，“化学预防”一词在本申请中被用于其最广泛的意义，即在部分治疗和纯粹预防的背景下使用。为了实现我们的目标，我们提出了两个具体的目标：(1)研究羽扇豆醇对雄激素非依赖性前列腺癌细胞的抑制作用，并确定其在细胞培养条件下的作用机制；(2)在动物模型上观察羽扇豆醇是否具有对雄激素不敏感的前列腺癌细胞的化学预防和/或化疗作用。我们相信，这一应用将为化学预防和治疗前列腺癌提供一种新的水果和蔬菜类药物，具有极其重要的价值。

DESCRIPTION (provided by applicant): It is estimated that 234,460 new prostate cancer cases will be diagnosed and approximately 27,350 prostate cancer-related deaths are predicted in the US alone in the year 2006. Persistence of isolated cancer cells (even after surgery and androgen-ablation therapy), their proliferation, androgen-independence and invasion to distant sites is the major cause of deaths in human prostate cancer patients. Aberration in the levels and functioning of multiple proteins or molecular pathways including beta catenin, nuclear factor kappa B and phosphotidyl inositol 3 kinase /Akt signaling network, has been associated with the androgen-independence, proliferation, invasion and chemoresistance of prostate cancer cells. Since most of the chemotherapeutic agents generally target a specific protein or a molecular pathway, they most often fail to inhibit the growth of advanced prostate cancer in preclinical and clinical settings. Thus, it is important to identify novel agents with an ability to target multiple molecular pathways. It is increasingly appreciated that chemoprevention through diet-based natural agents could be an effective approach to prevent and treat prostate cancer in humans. Based on our published studies and preliminary data, we believe that Lupeol, a non-nutrient and non-toxic natural agent present in strawberry, grapes, mango, figs, olive and vegetables, could be an ideal chemopreventive and therapeutic agent with an ability to act on multiple molecular pathways. We hypothesize that Lupeol has the potential to kill highly aggressive and chemoresistant prostate cancer cells while sparing normal cells, inhibit their proliferation and invasion through the modulation of beta catenin, nuclear factor kappa B and phosphotidyl inositol 3 kinase /Akt signaling network. It is important to emphasize that, consistent with current NCI opinion, the term "chemoprevention" is used in its broadest sense in this application, i.e. in a partially therapeutic as well as purely preventive context. To achieve our goal, we propose two specific aims: (1) to investigate the anti-proliferative potential of Lupeol against androgen-independent prostate cancer cells, and to define its mechanism of action under cell culture conditions and (2) to investigate whether Lupeol possesses the chemopreventive and/or chemotherapeutic effects against the tumorigenicity of androgen-insensitive prostate cancer cells in an animal model. We believe that this application will be extremely valuable in providing a novel fruit and vegetable based agent for chemoprevention and possibly for treating prostate cancer