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: 9060265
• 负责人: ASHOK K SALUJA
• 金额: $ 48.59万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060265
• 关键词: Animal Model; Apoptosis; Apoptotic; Applications Grants; BCL2 gene; Cancer Patient; Cancer cell line; Caspase; Cell Death; Cessation of life; Chinese People; Clinical Research; Combined Modality Therapy; Data; Development; Diterpenes; Evaluation; Family; Genetic Models; Human; Implant; Laboratories; Lead; Ligands; Literature; Lysosomes; Malignant neoplasm of pancreas; Mediating; Membrane; Methods; Modeling; Pancreas; Pathway interactions; Plants; Resistance; TNF gene; TNFSF10 gene; Testing; Therapeutic; Tissues; Tripterygium wilfordii; base; cancer cell; cancer therapy; design; inhibitor-of-apoptosis protein; insight; member; new therapeutic target; 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 NFκB 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 NFκB 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（由适用提供）：胰腺癌对传统和新型的抗癌疗法具有抵抗力，包括TRAIL（肿瘤坏死因子相关的凋亡诱导配体）。在我们的实验室中的研究表明，triptolide是一种从中国植物的Wilfordii植物中分离出来的化合物，敏感的胰腺癌细胞呈径径引起的细胞死亡。这些新颖的发现表明，Trail和Triptolide的结合可以作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械见解，并表明triptolide敏感性胰腺癌细胞通过两种不同的机制拖延了诱导细胞死亡：1）溶酶体对触发诱导的透化的敏感性； 2）通过废除TRAIL诱导的NFκB激活，从而抵消了由TRAIL诱导的亲生途径。在当前赠款提案的目标1中，将在三种独特但互补的胰腺癌模型中评估组合疗法的效率。 AIM 2和3旨在提供有关triptolide敏感性胰腺癌细胞尾部诱导细胞死亡的机制的见解。在AIM 2中，我们将评估triptolide下调Mcl-1，Bcl-2和Bcl-XL（Bcl-2家族的抗凋亡成员的新假设，该假设隔离了Bax/bak）。 Bax和Bak的释放，然后被TRAIL激活，使它们可以转移到溶酶体并诱导溶酶体膜通透性）。在AIM 3中，我们将评估新的假设，即triptolide通过抑制CIAP表达来下调试验诱导的NFκB激活。一旦揭开，三翼醇敏感的胰腺癌细胞的触发机制将导致新型药物靶标的发展。这些机械和翻译研究的成功完成最终将有助于计划策略，以将Triptolide与TRAIL相结合，以便可以将这种组合用于治疗胰腺癌。

项目成果

Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer.

• DOI: 10.1038/s41598-017-08447-3
• 发表时间: 2017-08-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: McGinn O;Gupta VK;Dauer P;Arora N;Sharma N;Nomura A;Dudeja V;Saluja A;Banerjee S
• 通讯作者: Banerjee S

Minnelide: a novel therapeutic that promotes apoptosis in non-small cell lung carcinoma in vivo.

• DOI: 10.1371/journal.pone.0077411
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Rousalova I;Banerjee S;Sangwan V;Evenson K;McCauley JA;Kratzke R;Vickers SM;Saluja A;D'Cunha J
• 通讯作者: D'Cunha J

Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in CD133+ tumor initiating cells.

• DOI: 10.18632/oncotarget.10838
• 发表时间: 2016-08-30
• 期刊: Oncotarget
• 作者: Nomura A;Dauer P;Gupta V;McGinn O;Arora N;Majumdar K;Uhlrich C 3rd;Dalluge J;Dudeja V;Saluja A;Banerjee S
• 通讯作者: Banerjee S

CD133 initiates tumors, induces epithelial-mesenchymal transition and increases metastasis in pancreatic cancer.

• DOI: 10.18632/oncotarget.3228
• 发表时间: 2015-04-10
• 期刊: Oncotarget
• 作者: Nomura A;Banerjee S;Chugh R;Dudeja V;Yamamoto M;Vickers SM;Saluja AK
• 通讯作者: Saluja AK

Impaired Synthesis of Stromal Components in Response to Minnelide Improves Vascular Function, Drug Delivery, and Survival in Pancreatic Cancer.

• DOI: 10.1158/1078-0432.ccr-15-1155
• 发表时间: 2016-01-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Banerjee S;Modi S;McGinn O;Zhao X;Dudeja V;Ramakrishnan S;Saluja AK
• 通讯作者: Saluja AK