Curcumin/TRAIL Combination Therapy of 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绿叶蔬菜、水果和豆制品，与亚洲男性患前列腺癌的几率较低有关。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，姜黄素/TRAIL（肿瘤坏死因子相关凋亡诱导配体）联合治疗可诱导前列腺癌细胞凋亡，其特征是膜联蛋白V结合，原aspase -3、-8和-9活化，线粒体释放细胞色素c。此外，前列腺癌细胞表达高水平的组成活性NF-KappaB，姜黄素抑制其表达。此外，siRNA或DN-lkappaBalpha （NF-KappaB抑制剂）抑制NF-KappaB可使前列腺肿瘤细胞对不含姜黄素的TRAIL增敏。这些结果使我们假设NF-kappaB介导前列腺癌细胞对TRAIL的抗性，姜黄素通过抑制NF-kappaB和NF-kappaB依赖的抗凋亡基因产物的表达使其对TRAIL诱导的凋亡敏感。拟开展的研究有三个目的：a)确定姜黄素抑制NF-KappaB活化的机制；b)确定姜黄素是否通过抑制NF-KappaB依赖性抗凋亡的Bcl-2、Bcl-xL和凋亡蛋白家族成员抑制剂（lAPs）使肿瘤细胞对TRAIL增敏；c)探索姜黄素/TRAIL联合方案对激素难治性前列腺肿瘤异种移植的治疗效果。了解姜黄素抑制NF-KappaB激活和使前列腺癌细胞对TRAIL敏感的机制，可以为开发这种新的治疗策略铺平道路，作为前列腺癌常规治疗的辅助手段。

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.