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（由申请人提供）：前列腺癌是美国癌症死亡的第二大原因，仅由肺癌超过。流行病学研究表明，饮食在预防前列腺癌中起着至关重要的作用。富含多酚化合物的深绿色叶蔬菜，水果和大豆产品的高摄入量与亚洲男性的前列腺癌低率有关。姜黄素是香料姜黄中的黄色颜料，已显示出表现出化学预防和肿瘤生长抑制活性。我们的初步数据表明，姜黄素/TRAR（肿瘤坏死因子相关凋亡诱导配体）治疗诱导前列腺癌细胞系中的凋亡，这些细胞系的特征是膜联蛋白V的激活，Procaspases-3，-8和-9的激活，以及-9的释放，以及从MiToChrome c CoChromeChromeChromeChromeChromeChromeChromeChromeChromeChondroceChromoChondrira的释放。此外，前列腺癌细胞表达高水平的组成型活性NF-kappab，姜黄素抑制。此外，siRNA或DN-LKAPPABALPHA（NF-kappab抑制剂）对NF-kappab的抑制作用使前列腺肿瘤细胞敏感无姜黄素。这些结果使我们假设NF-kappab介导了前列腺癌细胞的耐药性，并且姜黄素通过抑制NF-kappab和NF-kappab依赖性抗蛋白质基因产物的表达来使它们敏感到触发诱导的细胞凋亡。提出的研究具有三个目标：a）确定姜黄素抑制NF-kappab激活的机制，b）确定姜黄素是否通过抑制NF-kappab依赖性抗凋亡Bcl-2，Bcl-XL，BCl-XL，BCL-XL，BCL-XL，以及commentife fresposion frespection and commentife feffer feffer feffer feffer feff-bcl-2姜黄素/越野前列腺异种移植物针对激素 - 难治性前列腺异种移植。了解姜黄素抑制NF-kappab激活并使前列腺癌细胞敏感的机制可能为制定这种新型治疗策略作为前列腺癌常规治疗方法的辅助性铺平道路。