学者简介以及论文摘要
拉杰什·阿加瓦尔教授：
医学博士、美国科罗拉多大学药物科学系教授兼副主任、科罗拉多大学肿瘤中心癌症预防和控制项目联合领导人。
Inositol Hexaphosphate and Prostate Cancer: Efficacy and Mechanism
Rajesh Agarwal Professor University of Colorado USA
Prostate cancer (PCA) is the most frequently diagnosed invasive malignancy and second leading cause of cancer-associated deaths in the males in the United States. PCA growth and progression involve an aberrant cell cycle progression following gradual accumulation of genetic and epigenetic changes over a period of years. Several mechanisms including a decrease in and/or loss of cyclin-dependent kinase inhibitor (CDKI) function contribute to these events, suggesting that an induction in CDKI level and/or gain in its function could be one of the most promising approaches for PCA prevention, growth control and/or therapy. Inositol hexaphosphate (IP6) is a nutrient constituting 6.4% (w/w) or even higher levels in most cereals, legumes, nuts, oil seeds and soybean, and also taken orally as an over-the-counter dietary/ nutrient supplement for its several health benefits without any known toxicity. In PCA cell culture, completed studies by us show that IP6 up-regulates CDKI Kip1/p27 and Cip1/p21 levels together with their increased interaction with CDKs causing inhibition in the kinase activity of CDKs and associated cyclins. These effects of IP6 also caused a G1 arrest, strong inhibition of human and rodent PCA cell growth, and induction of their apoptotic death. No such IP6 effects were observed; however, in non-neoplastic human prostate epithelial cells. Additional studies using siRNA show that IP6-caused G1 arrest in DU145 cells requires up-regulation of p27 and p21. Based on these findings, we performed more studies to answer the question whether p27 and/or p21 induction is required for cell cycle arrest and apoptotic death by IP6 in its efficacy against PCA. Employing genetic and pharmacological approaches, our studies show that indeed p27 and p21 are required for IP6 efficacy against PCA in both cell culture and nude mouse xenograft model where oral feeding of IP6 strongly inhibited human PCA xenograft growth without toxicity. Furthermore, our completed studies in a spontaneous transgenic mouse model of prostate cancer (namely TRAMP model) also show that IP6 feeding suppresses growth and progression of PCA via its ability to alter tumor vascularity and the energy generating metabolic events in the tumor cells, which are essential for tumor sustenance. Since these mechanistic events eventually result in arrest of tumor grade at neoplastic stages, this protective effect of IP6 against PCA might have clinical implications in controlling the malignancy at an early stage. In more recent studies, we observed that the anti-PCA effects of IP6 are also associated with its potential to eradicate prostate cancer stem cell pool, which is now recognized to be involved in the initiation, progression, relapse, and therapy-resistance of PCA. Together, these findings suggest the practical and translational potential of IP6 treatment in suppressing growth and progression of PCA in humans, and advocate for a potential clinical trial of IP6 in PCA patients, which may improve their morbidity and survival time.
IP6和前列腺癌: 功效与机理
——拉杰什.阿加瓦尔教授 美国科罗拉多大学
前列腺癌(PCA)是最常见的侵袭性恶性肿瘤，也是美国男性癌症死亡的第二大原因。随着时间的推移，遗传和表观遗传变化逐渐积累，PCA的生长和进展涉及细胞周期的异常进展。包括减少和/或损失的细胞周期蛋白依赖性激酶抑制剂(CDKI)功能的多种机制导致了这些事件，表明CDKI感应水平和/或获得感应功能可能是最有前途的预防前列腺癌，控制其生长和/或治疗的方法。肌醇六磷酸（IP6）是一种存在于大多数谷类，豆类，坚果，种子和大豆油中营养重比构成6.4%甚至更高的营养物，并作为口服非处方膳食营养补充，对健康有益且无任何已知毒性。在前列腺癌细胞培养完整研究中，我们发现IP6对CDKI Kip1/p27和Cip1/p21的水平有上调作用，同时增加与CDKs互动产生对CDKs和相关细胞周期蛋白激酶活性的抑制。IP6这些作用还引起G1期阻滞，强力抑制人类和啮齿类动物的癌细胞生长并诱导其凋亡。然而在非肿瘤性前列腺上皮细胞没有发现IP6这样的作用。小干扰（siRNA）进一步的研究表明，IP6 在DU145细胞中引起G1期阻滞需要p27和p21基因调控。基于这些发现，我们进行更多的研究来回答是否需要p27和/或p21感应，通过IP6对PCA起疗效来完成细胞周期阻滞和细胞凋亡这个问题。用基因和药理学方法，事实上在细胞培养和裸鼠移植典型研究中，我们的研究表明，确实需要p27和p21来实现IP6对PCA起疗效，并且口服IP6强力地抑制人类前列腺癌移植瘤的生长而不产生毒性。此外，我们一个自发性转基因小鼠模型（即流浪汉模式）的前列腺癌的完整研究，还显示IP6摄食抑制PCA生长和发展，通过改变肿瘤细胞中必不可少的肿瘤血管生成和能量代谢活动。由于这些机理事件最终将肿瘤阻滞在新生阶段，这也保护了IP6对PCA起作用，可能具有将恶性肿瘤控制在初期阶段的临床意义。在最近的研究中，我们观察到IP6抗前列腺癌的作用与其潜在的根除前列腺癌干细胞池功能相关联，这是目前公认的对PCA的初期、进展、复发和抵抗治疗有影响的因素。另外，这些研究结果表明IP6在抑制PCA的生长和发展实际和交流潜力治疗作用，倡导IP6在前列腺癌患者中进行一种潜在临床实验，可改善其发病率和延长生存期。
