Prostate Cancer Prevention by Diallyl Trisulfide

描述（由申请人提供）：本转化研究项目基于二烯丙基三硫化物（DATS），一种大蒜衍生的有机硫化合物，可用于抑制前列腺癌的发生和/或进展，前列腺癌是美国男性癌症相关死亡的第二大原因。对DATS抗前列腺癌进行系统临床前评估的基本原理来自流行病学数据和我们最近完成的初步研究结果，这使我们假设DATS能够抑制前列腺癌的发生和/或进展，因为它能够(a)引起G2/M期细胞周期阻滞，涉及Cdc25C的Ser-216磷酸化，以及(b)通过激活c-Jun n末端激酶（JNKs）引起caspase介导的细胞凋亡。我们建议通过以下方式来检验这一假设：(1)以PC-3和DU145人前列腺癌细胞为细胞模型，确定Cdc25C磷酸化在dats诱导的G2/M期细胞周期阻滞中的功能意义和机制；(2)以PC-3和DU145细胞为模型，确定dats诱导的JNKs活化的机制；(3)确定内源性（线粒体介导的caspase-9激活）和外源性（死亡受体介导的caspase-8激活）caspase途径在PC-3和DU145细胞中诱导凋亡的相对贡献；(4)确定口服DATS对裸鼠体内PC-3和DU145异种移植物生长的影响；(5)确定DATS在体内预防TRAMP小鼠前列腺肿瘤发生的作用。在Specific Aims 4和5中，我们将分析对照和DATS处理小鼠的肿瘤组织的凋亡指数、细胞周期和凋亡调节蛋白的水平，以确定DATS诱导的细胞内分子变化（Aims 1-3）与体内作用的关联程度。总之，本申请中提出的研究将(a)确定DATS抑制人类前列腺癌细胞增殖的机制，这可能导致在未来临床试验中潜在有用的基于机制的生物标志物的鉴定；(b)使用适当的动物模型确定DATS对前列腺癌的疗效，这是启动临床试验以确定DATS对人类前列腺癌活性的先决条件。从长远来看，拟议研究的结果可能会导致基于dats的预防和/或治疗人类前列腺癌的策略。

DESCRIPTION (provided by applicant): This translational research project is based on the premise that diallyl trisulfide (DATS), a garlic-derived organosulfur compound, may be used to inhibit onset and/or progression of prostate cancer, which is the second leading cause of cancer related deaths among men in the United States. The rationale for a systematic preclinical evaluation of DATS against prostate cancer derives from epidemiological data and the results of our recently completed preliminary studies, which led us to hypothesize that DATS will inhibit onset and/or progression of prostate carcinogenesis due to its ability to (a) cause G2/M phase cell cycle arrest involving Ser-216 phosphorylation of Cdc25C, and (b) cause caspase-mediated apoptosis through activation of c-Jun N-terminal kinases (JNKs). We propose to test this hypothesis by: (1) determining the functional significance and mechanism of Cdc25C phosphorylation in DATS-induced G2/M phase cell cycle arrest using PC-3 and DU145 human prostate cancer cells as a cellular model, (2) determining the mechanism of DATS-induced activation of JNKs using PC-3 and DU145 cells, (3) determining the relative contribution of intrinsic (mitochondria mediated activation of caspase-9) and extrinsic (death-receptor mediated activation of caspase-8) caspase pathways in apoptosis induction by DATS using PC-3 and DU145 cells, (4) determining the effect of oral administration of DATS on growth of PC-3 and DU145 xenografts in vivo in nude mice, and (5) determining in vivo efficacy of DATS for prevention of prostate tumorigenesis in TRAMP mice. In Specific Aims 4 and 5, the tumor tissues from control and DATS treated mice will be analyzed for apoptosis index and levels of cell cycle and apoptosis regulating proteins to determine the extent to which DATS-induced molecular changes observed in cells (Aims 1-3) correlate with its effect in vivo. In summary, the studies proposed in this application will (a) define the mechanism(s) by which DATS inhibits proliferation of human prostate cancer cells, which could lead to identification of mechanism-based biomarkers potentially useful in future clinical trials, and (b) determine efficacy of DATS against prostate cancer using appropriate animal models, which is a prerequisite for initiation of clinical trials to determine activity of DATS against prostate cancer in humans. In the long run, the results of the proposed studies could lead to DATS-based strategies for prevention and/or treatment of human prostate cancers.