Chemosensitization of Pancreatic Cancer Cells by Curcumin and Vitamin D Receptor

姜黄素和维生素 D 受体对胰腺癌细胞的化疗增敏作用

• 批准号: 8508551
• 负责人: Timothy Yen
• 金额: $ 19.41万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508551
• 关键词: Address; Adenocarcinoma; Agonist; Alleles; Beryllium; Biological Factors; Calcium; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Line; Cell Survival; Cells; Cessation of life; Chemosensitization; Clinical; Collection; Combined Modality Therapy; Complex; Consensus; Curcumin; Cytotoxic agent; DNA Damage; DNA damage checkpoint; Data; Diagnosis; Diagnostic; Disease; Dose; Doxorubicin; Early Diagnosis; Etoposide; Exhibits; Fluorouracil; Genes; Genetic Transcription; Homeostasis; In Vitro; Leucovorin; Libraries; Life Expectancy; Ligands; Link; Malignant neoplasm of pancreas; Mediating; Methods; Mitotic; Molecular; Nuclear Hormone Receptors; Operative Surgical Procedures; Pancreas; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Physiologic calcification; Play; Promoter Regions; Property; Proteins; RNA Interference; Radiation; Regimen; Regulation; Relative (related person); Resistance; Role; Site; Small Interfering RNA; Staging; Testing; Time; Toxic effect; Transactivation; Treatment outcome; Tumeric; Tumor Cell Line; United States; Vitamin D; Vitamin D Analog; Vitamin D3 Receptor; base; cancer cell; cancer therapy; cell killing; chemosensitizing agent; chemotherapy; clinical efficacy; gemcitabine; genome-wide; improved; inhibitor/antagonist; irinotecan; killings; meetings; mutant; nucleoside analog; outcome forecast; oxaliplatin; pancreatic cancer cells; pancreatic neoplasm; promoter; public health relevance; research study; response; sobriety; statistics; success; treatment strategy; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer (adenocarcinoma) is the fourth leading cause of cancer deaths in the United States and carries the worst prognosis, with median life expectancy of less than a year. As the disease is diagnosed at a late stage, treatment options are limited. Surgery only modestly improves life expectancy. Pancreatic adenocarcinomas are highly refractile to conventional chemotherapies. Relative to radiation and paclitaxal, gemcitabine is recognized to be the more efficacious drug. The sobering statistic, however, is that gemcitabine only extends patient survival by several months over other therapies. The molecular basis for chemoresistance is likely to be highly complex, as combination therapies with gemcitabine have met with limited success. There is an urgent need to identify methods to enhance sensitivity of pancreatic cancer cells to chemotherapy. In preliminary experiments, we conducted a genome-wide siRNA screen to identify genes responsible for gemcitabine sensitivity. We identified a small collection of genes that include the vitamin D receptor (VDR) and various associated interacting and downstream genes. We have validated VDR to be an important determinant of gemcitabine sensitivity in vitro. Using an independent set of VDR siRNAs, gemcitabine sensitization was achieved in two cell lines (Panc1 and BXPC3) as determined by clonogenic survival. VDR is a nuclear hormone receptor that is best known for its ability to regulate genes important for calcium homeostasis and mineralization of bone. However, the activities of VDR are vast and complex as its also known for its anti-proliferative properties and is being tested in combination with cytotoxic agents for cancer treatment. We have found that VDR is required for the formation of DNA damaged foci in cells treated with DNA damaging agents. Chemosensitization of cells lacking VDR may therefore be due to disruption of DNA damage response that promote cell survival. This proposal seeks to extend the recent finding that the natural compound curcumin is a ligand for VDR. The use of curcumin as a chemosensitizer is well documented but its mode of action remains obscure. These observations combined with our preliminary data leads us to propose that curcumin acts via VDR to enhance chemosensitzation of pancreatic cancer cells. Furthermore, as the cytoprotective actions of VDR is known to depend on the context of mutant p53 status, the impact on curcumin induced chemosensitization will also be assessed. Our studies have significant clinical ramifications as a large proportion of pancreatic tumors and cell lines express mutant p53. The status of p53 may dictate whether to treat cancer patients with a vitamin D analog or antagonist and curcumin along with standard chemotherapy.

描述（由申请人提供）：胰腺癌（腺癌）是美国癌症死亡的第四大原因，预后最差，中位预期寿命不到一年。由于这种疾病是在晚期被诊断出来的，因此治疗选择有限。手术只能适度提高预期寿命。胰腺癌对常规化疗具有高度敏感性。相对于放疗和紫杉醇，吉西他滨被认为是更有效的药物。然而，令人清醒的统计数据是，吉西他滨仅比其他疗法延长患者生存期数月。化疗耐药的分子基础可能非常复杂，因为吉西他滨联合治疗的成功率有限。迫切需要确定提高胰腺癌细胞对化疗敏感性的方法。 在初步实验中，我们进行了全基因组siRNA筛选，以确定负责吉西他滨敏感性的基因。我们发现了一小部分基因， 维生素D受体（VDR）和各种相关的相互作用和下游基因。我们已经验证了VDR是体外吉西他滨敏感性的重要决定因素。使用一组独立的VDR siRNA，在两种细胞系（Panc1和BXPC 3）中实现了吉西他滨致敏，如通过克隆形成存活所确定的。VDR是一种核激素受体，最为人所知的是其调节对钙稳态和骨矿化重要的基因的能力。然而，VDR的活性是巨大的和复杂的，因为它也已知其抗增殖特性，并且正在与细胞毒性剂组合用于癌症治疗进行测试。我们已经发现VDR是用DNA损伤剂处理的细胞中DNA损伤灶形成所必需的。因此，缺乏VDR的细胞的化学致敏性可能是由于促进细胞存活的DNA损伤反应的破坏。 该提案旨在扩展最近的发现，即天然化合物姜黄素是VDR的配体。姜黄素作为化疗增敏剂的使用是有据可查的，但其作用方式仍不清楚。这些观察结果与我们的初步数据相结合，使我们提出姜黄素通过VDR增强胰腺癌细胞的化学增敏作用。此外，由于已知VDR的细胞保护作用取决于突变型p53状态的背景，因此还将评估对姜黄素诱导的化学增敏作用的影响。我们的研究具有重要的临床意义，因为大部分胰腺肿瘤和细胞 细胞系表达突变型p53。p53的状态可能决定是否用维生素D类似物或拮抗剂和姜黄素沿着标准化疗治疗癌症患者。