Allium Compounds in Control of Human Prostate Cancer

控制人类前列腺癌的葱化合物

• 批准号: 6624192
• 负责人: JOHN T PINTO
• 金额: $ 16.1万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624192
• 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）这项探索性赠款旨在 确立大蒜中葱属衍生物在控制人类疾病中新作用 前列腺癌作为抗雄激素。我们的初步观察显示 当将雄激素应答的人前列腺癌细胞（LNCaP） 在体外用葱衍生物，发生两个事件：（a）增殖 LNCaP细胞的比率显著降低，并且（B）睾酮浓度 在细胞生长的培养基中迅速减少， 在细胞本身。此外，当睾丸激素被添加回 培养基的LNCaP细胞先前暴露于葱衍生物，减少 细胞增殖的初始速率仅部分恢复。这些 初步结果强烈提示，大蒜诱导的细胞抑制 睾丸激素的增殖和加速排出是有联系的。我们 假设葱属衍生物增加睾酮消失， 加速转化为无活性代谢物，从而降低了 前列腺的睾丸激素。为了验证这个假设的有效性，我们 应测量睾酮向双氢睾酮（DHT）的转化率， 一种更有效的代谢物，通过5-α还原酶， 一系列无活性的睾酮代谢产物，通过GC-MS方法测定。 在进行这些实验的同时，我们将确定 通过葱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停滞。我们将确定在细胞周期中 是否发生生长抑制，是否诱导细胞凋亡，以及是否 在后来的实验中，我们发现了特定信号传导蛋白的变化， 将研究葱衍生物对调节蛋白的影响， 与这些条件有关的是， (i.e., cyclin B，cdk 2）。这些研究将在第二年延长 研究葱属衍生物对人前列腺癌细胞（LNCaP）的作用 C4-2），显示雄激素受体，但对其营养无反应 方面的影响.总之，LNCaP和LNCaP C4-2细胞系应作为 适当的模型，分别为早期前列腺癌， 雄激素敏感性和晚期前列腺癌，在很大程度上对 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的和有效的， 并将导致一个创新性的进步， 修改和前列腺癌。