Triptolide Augments Death Receptor Mediated Apoptosis in Pancreatic Cancer

雷公藤内酯醇增强死亡受体介导的胰腺癌细胞凋亡

• 批准号: 8676485
• 负责人: ASHOK K SALUJA
• 金额: $ 46.68万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-06 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676485
• 关键词: Animal Model; Apoptosis; Apoptotic; Applications Grants; BCL2 gene; Cancer Patient; Cancer cell line; Caspase; Cell Death; Cells; Cessation of life; Chinese People; Clinical Research; Combined Modality Therapy; Data; Development; Diterpenes; Drug Targeting; Evaluation; Family; Genetic Models; Human; Implant; Laboratories; Lead; Ligands; Literature; Lysosomes; Malignant neoplasm of pancreas; Mediating; Membrane; Methods; Modeling; Pancreas; Pathway interactions; Plants; Resistance; TNFSF10 gene; Testing; Therapeutic; Tissues; Tripterygium wilfordii; Tumor Necrosis Factor-alpha; base; cancer cell; cancer therapy; design; inhibitor-of-apoptosis protein; insight; member; novel; pancreatic cancer cells; prevent; protein expression; receptor; response; success; translational study; triptolide; tumor growth

DESCRIPTION (provided by applicant): Pancreatic cancer is resistant to conventional as well as novel anti-cancer therapies including TRAIL (Tumor Necrosis Factor-Related Apoptosis Inducing Ligand). Studies in our laboratories show that triptolide, a compound isolated from the Chinese plant Tripterygium wilfordii, sensitizes pancreatic cancer cells to cell death caused by TRAIL. These novel findings suggest that the combination of TRAIL and triptolide can emerge as an effective therapeutic strategy for pancreatic cancer. Our preliminary studies also provide some mechanistic insights and suggest that triptolide sensitizes pancreatic cancer cells to TRAIL induced cell death by two different mechanisms: 1) by sensitization of the lysosomes to TRAIL induced permeabilization; and 2) by abrogating TRAIL induced NF?B activation, thus counteracting pro-survival pathways induced by TRAIL. In Aim 1 of the current grant proposal, the efficacy of combination therapy will be evaluated in three unique but complementary animal models of pancreatic cancer. Aims 2 and 3 are designed to provide insights into the mechanism by which triptolide sensitizes pancreatic cancer cells to TRAIL induced cell death. In Aim 2 we will evaluate the novel hypothesis that triptolide downregulates Mcl-1, Bcl-2 and Bcl-xl (anti- apoptotic members of Bcl-2 family which sequester Bax/Bak). Release of Bax and Bak, which are then activated by TRAIL, allows them to translocate to lysosomes and induce lysosomal membrane permeabilization). In Aim 3 we will evaluate the novel hypothesis that triptolide downregulates TRIAL induced NF?B activation by inhibiting cIAP expression. Once unraveled, the mechanisms by which triptolide sensitizes pancreatic cancer cells to TRAIL will lead to the development of novel drug targets. Successful completion of these mechanistic and translational studies will eventually help in planning strategies to combine triptolide with TRAIL so that this combination can be used for the treatment of pancreatic cancer.

描述（由申请人提供）：胰腺癌对传统的以及新型的抗癌疗法具有耐药性，包括TRAIL（肿瘤坏死因子相关细胞凋亡诱导配体）。我们实验室的研究表明，雷公藤甲素（一种从中国植物雷公藤中分离出来的化合物）可使胰腺癌细胞对 TRAIL 引起的细胞死亡敏感。这些新发现表明 TRAIL 和雷公藤甲素的组合可以成为胰腺癌的有效治疗策略。我们的初步研究还提供了一些机制见解，并表明雷公藤甲素通过两种不同的机制使胰腺癌细胞对 TRAIL 诱导的细胞死亡敏感：1）通过溶酶体对 TRAIL 诱导的透化作用敏感； 2)通过消除TRAIL诱导的NFκB激活，从而抵消TRAIL诱导的促生存途径。在当前拨款提案的目标 1 中，将在三种独特但互补的胰腺癌动物模型中评估联合疗法的疗效。目标 2 和 3 旨在深入了解雷公藤内酯醇使胰腺癌细胞对 TRAIL 诱导的细胞死亡敏感的机制。在目标 2 中，我们将评估雷公藤甲素下调 Mcl-1、Bcl-2 和 Bcl-xl（Bcl-2 家族的抗凋亡成员，隔离 Bax/Bak）的新假设。 Bax 和 Bak 的释放随后被 TRAIL 激活，使它们能够易位至溶酶体并诱导溶酶体膜透化。在目标 3 中，我们将评估雷公藤甲素通过抑制 cIAP 表达下调 TRIAL 诱导的 NF?B 激活的新假设。一旦揭开，雷公藤内酯醇使胰腺癌细胞对 TRAIL 敏感的机制将导致新药物靶点的开发。成功完成这些机制和转化研究最终将有助于制定雷公藤甲素与 TRAIL 联合用药的策略，从而使该联合用药可用于胰腺癌的治疗。