Allium Compounds in Control of Human Prostate Cancer

控制人类前列腺癌的葱化合物

• 批准号: 6472930
• 负责人: JOHN T PINTO
• 金额: $ 16.03万
• 依托单位: INSTITUTE FOR CANCER PREVENTION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6472930
• 关键词: allyl compound; androgen inhibitor; androstane compound; angiosperms; antineoplastics; apoptosis; athymic mouse; cyclin dependent kinase; cyclins; cytotoxicity; dihydrotestosterone; estradiol; flow cytometry; glutathione; neoplasm /cancer nutrition therapy; nonhuman therapy evaluation; nutrition aspect of cancer; nutrition related tag; plant extracts; prostate neoplasms; prostate specific antigen; sulfides; testosterone; western blottings

DESCRIPTION: (provided by the applicant) This exploratory grant seeks to establish a novel role for allium derivatives from garlic in control of human prosta cancer by acting as anti-androgens. Our preliminary observations reveal that when androgen-responsive human prostate cancer cells (LNCaP) are incubated with allium derivatives in vitro, two events take place: (a) the proliferation rate of the LNCaP cells is markedly reduced and (b) testosterone concentration rapidly decreases in both the media in which the cells are growing as well as in the cells themselves. Furthermore, when testosterone is added back to the media of LNCaP cells previously exposed to allium derivatives, the decrease in initial rate of cell proliferation is only partially restored. These preliminary results strongly suggest that allium-induced inhibition of cell proliferation and accelerated removal of testosterone are linked. We hypothesize that allium derivatives increase testosterone disappearance by accelerating conversion to inactive metabolites thereby diminishing the action of testosterone on the prostate. To test I validity of this hypothesis, we shall measure the conversion rate of testosterone to dihydrotestosterone (DHT), a more potent metabolite, through 5-alpha reductase, and the formation rate of a series of inactive testosterone metabolites, a determined by GC-MS methods. Concurrent with these experiments, we shall determine the mechanism of inhibition of growth of human prostat cancer cells by allium derivatives, whether by apoptosis or cytostasis. We shall determine where in the cell cycle growth inhibition occurs, whether or not apoptosis is induced, and whether changes in specific signal transduction proteins occ in later experiments, we shall examine effects of allium derivatives on regulatory proteins most likely to be relevant unc these conditions in modifying cell cycle transcription (i.e., cyclin B, cdk 2). These studies will then be extended in the second year to examine effects of allium derivatives on human prostate cancer cells (LNCaP C4-2) that exhibit androgen receptors but are non-responsive to its trophic effects. Together, the LNCaP and LNCaP C4-2 cell lines should serve as appropriate models, respectively, for early prostate cancer that is androgen-sensitive and later prostate cancer that is largely unresponsive to androgen manipulations. These studies should provide a creative approach to prevention and control of prostate cancer that is feasible and cosi effective, and should lead to an innovative advance in correlating certain dietary modifications and prostate cancer.

描述：（由申请人提供）这项探索性资助旨在确立大蒜葱衍生物在控制人类疾病方面的新作用。 前列腺癌通过作为抗雄激素发挥作用。我们的初步观察表明 当雄激素反应性人前列腺癌细胞 (LNCaP) 孵育时 在体外，葱衍生物会发生两个事件：（a）增殖 LNCaP 细胞的比率显着降低，并且 (b) 睾酮浓度 在细胞生长的培养基以及 在细胞本身。此外，当睾丸激素重新添加到体内时 先前暴露于葱衍生物的 LNCaP 细胞的培养基中， 细胞增殖的初始速率仅部分恢复。这些 初步结果强烈表明，葱诱导的细胞抑制作用 增殖和睾酮的加速去除是相关的。我们 假设葱衍生物通过以下方式增加睾酮消失 加速转化为无活性代谢物，从而减弱其作用 睾酮对前列腺的作用。为了检验这个假设的有效性，我们 应测量睾酮到二氢睾酮（DHT）的转化率， 通过 5-α 还原酶产生更有效的代谢物，并且形成率 一系列非活性睾酮代谢物，通过 GC-MS 方法测定。 在进行这些实验的同时，我们将确定其机制 葱属衍生物抑制人前列腺癌细胞的生长， 无论是通过细胞凋亡还是细胞抑制。我们将确定细胞周期中的哪个位置 是否发生生长抑制，是否诱导细胞凋亡，以及是否 在后面的实验中，我们发现特定信号转导蛋白occ的变化 应检查葱属衍生物最有可能对调节蛋白的影响 与修改细胞周期转录相关的这些条件 （即细胞周期蛋白 B、cdk 2）。这些研究将在第二年扩展 检查葱衍生物对人类前列腺癌细胞的影响 (LNCaP C4-2）表现出雄激素受体但对其营养无反应 影响。 LNCaP 和 LNCaP C4-2 细胞系一起应作为 分别针对早期前列腺癌的适当模型 雄激素敏感和后来的前列腺癌对雄激素基本上没有反应 雄激素操纵。这些研究应该提供一种创造性的方法 预防和控制前列腺癌是可行且有效的， 并应导致在关联某些饮食方面取得创新进展 修饰和前列腺癌。