Curcumin/TRAIL Combination Therapy of Prostate Cancer

姜黄素/TRAIL联合治疗前列腺癌

• 批准号: 6917402
• 负责人: SUBHASH C GAUTAM
• 金额: $ 15.48万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917402
• 关键词: BCL2 gene /protein; I kappa B beta; SDS polyacrylamide gel electrophoresis; antineoplastics; apoptosis; combination chemotherapy; combination therapy; gene expression; growth inhibitors; laboratory mouse; ligands; medicinal plants; neoplasm /cancer chemotherapy; neoplastic cell; nonhuman therapy evaluation; nuclear factor kappa beta; phosphatidylinositol 3 kinase; plant extracts; prostate neoplasms; transcription factor; transfection; tumor necrosis factor alpha; western blottings

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，仅次于肺癌。 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。大量摄入富含多酚化合物的深绿色叶蔬菜、水果和豆制品与亚洲男性前列腺癌的低发病率有关。姜黄素，香料姜黄中的黄色色素，已被证明具有化学预防和肿瘤生长抑制活性。我们的初步数据表明，联合姜黄素/TRAIL（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的凋亡，其特征在于结合膜联蛋白V，激活前半胱氨酸蛋白酶-3，8和9，并释放细胞色素c从线粒体。此外，前列腺癌细胞表达高水平的组成型活性NF-κ B，其被姜黄素抑制。此外，通过siRNA或DN-lkappaB α（NF-κ B抑制剂）抑制NF-κ B使前列腺肿瘤细胞对TRAIL敏感而不需要姜黄素。这些结果使我们假设NF-κ B介导前列腺癌细胞对TRAIL的抗性，姜黄素通过抑制NF-κ B和NF-κ B依赖性抗凋亡基因产物的表达使其对TRAIL诱导的凋亡敏感。所提出的研究具有三个目标：a）确定姜黄素抑制NF-κ B活化的机制，B）确定姜黄素是否通过抑制NF-κ B依赖性抗凋亡Bcl-2、Bcl-xL和凋亡蛋白家族成员（IAP）的抑制剂而使肿瘤细胞对TRAIL敏感，以及c）探索姜黄素/TRAIL组合方案对难治性前列腺肿瘤异种移植物的治疗功效。了解姜黄素抑制NF-KappaB活化和使前列腺癌细胞对TRAIL敏感的机制，可以为开发这种新型治疗策略作为前列腺癌常规治疗的辅助手段铺平道路。