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Curcumin/TRAIL Combination Therapy of Prostae Cancer

姜黄素/TRAIL联合治疗前列腺癌

基本信息

批准号：
7034543
负责人：
SUBHASH C GAUTAM
金额：
$ 18.14万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2008-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer deaths in the U.S., exceeded only by lung cancer. Epidemiological studies suggest that diet plays a crucial role in preventing prostate cancer. High intake of dark green leafy vegetables, fruits and soy products, which are rich in polyphenolic compounds, has been linked to low rate of prostate cancer in Asian men. Curcumin, the yellow pigment in the spice turmeric, has been shown to exhibit chemopreventive and tumor growth inhibitory activity. Our preliminary data indicate that combined curcumin/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) treatment induces apoptosis in prostate cancer cell lines characterized by binding of annexin V, activation of procaspases-3, -8, and -9, and the release of cytochrome c from mitochondria. In addition, prostate cancer cells express high levels of constitutively active NF-KappaB, which is inhibited by curcumin. Moreover, inhibition of NF-KappaB by siRNA or DN-lkappaBalpha (NF-KappaB inhibitor) sensitizes prostate tumor cells to TRAIL without curcumin. These results lead us to hypothesize that NF-kappaB mediates resistance of prostate cancer cells to TRAIL, and curcumin sensitizes them to TRAIL-induced apoptosis by inhibiting NF-KappaB and the expression of NF-kappaB dependent antiapoptotic gene products. The proposed studies have three goals: a) to determine the mechanism by which curcumin inhibits NF-KappaB activation, b) to determine whether curcumin sensitizes tumor cells to TRAIL by inhibiting NF-KappaB-dependent antiapoptotic Bcl-2, Bcl-xL, and inhibitors of apoptosis protein family members (lAPs), and c) to explore therapeutic efficacy of combined curcumin/TRAIL regimen against hormone-refractory prostate tumor xenografts. Understanding the mechanism by which curcumin inhibits NF-KappaB activation and sensitizes prostate cancer cells to TRAIL could pave the way for developing this novel treatment strategy as an adjunct to the conventional treatments for prostate cancer.

描述(申请人提供)：前列腺癌是美国癌症死亡的第二大原因，仅次于肺癌。流行病学研究表明，饮食在预防前列腺癌方面起着至关重要的作用。大量摄入富含多酚化合物的深绿色叶类蔬菜、水果和豆制品与亚洲男性前列腺癌发病率较低有关。姜黄素是香料姜黄中的黄色色素，已被证明具有化学预防和抑制肿瘤生长的活性。我们的初步数据表明，姜黄素/TRAIL(肿瘤坏死因子相关的凋亡诱导配体)联合治疗可诱导前列腺癌细胞株的凋亡，其特征是与膜联蛋白V结合，激活原天冬氨酸酶-3，-8和-9，并从线粒体释放细胞色素c。此外，前列腺癌细胞表达高水平的结构性活性的核因子-kappaB，这是被姜黄素抑制的。此外，用siRNA或dN-1kappaBalpha(核因子-kappaB抑制剂)抑制NF-kappaB可使前列腺癌细胞对不含姜黄素的TRAIL敏感。这些结果使我们推测，NF-kappaB介导了前列腺癌细胞对TRAIL的耐药性，姜黄素通过抑制NF-kappaB及其依赖的抗凋亡基因产物的表达而使其对TRAIL诱导的细胞凋亡敏感。这些研究有三个目的：a)确定姜黄素抑制核因子-kappaB活化的机制；b)确定姜黄素是否通过抑制依赖于核因子-kappaB的抗凋亡蛋白Bcl2、bclxl和凋亡抑制蛋白家族成员(LAPS)来增强肿瘤细胞对TRAIL的敏感性；c)探讨姜黄素/TRAIL联合方案治疗激素非依赖性前列腺癌移植瘤的疗效。了解姜黄素抑制核因子-kappaB活化和使前列腺癌细胞对TRAIL增敏的机制，将为开发这一新的治疗策略作为前列腺癌常规治疗的辅助手段铺平道路。