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

基本信息

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
项目类别：
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

项目摘要

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）是美国第四大癌症死亡原因，预后最差，中位预期寿命不到一年。由于该疾病已处于晚期诊断，治疗选择有限。手术只能适度提高预期寿命。胰腺腺癌对传统化疗具有很强的抵抗力。相对于放射和紫杉醇，吉西他滨被认为是更有效的药物。然而，令人警醒的统计数据是，与其他疗法相比，吉西他滨只能将患者的生存期延长几个月。化疗耐药的分子基础可能非常复杂，因为吉西他滨的联合疗法取得的成功有限。迫切需要找到增强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，以确定与吉西他滨敏感性相关的基因。我们鉴定了一小部分基因，其中包括维生素 D 受体 (VDR) 和各种相关的相互作用基因和下游基因。我们已验证 VDR 是吉西他滨体外敏感性的重要决定因素。使用一组独立的 VDR siRNA，通过克隆形成存活确定，在两种细胞系（Panc1 和 BXPC3）中实现了吉西他滨致敏。 VDR 是一种核激素受体，以其调节对钙稳态和骨矿化重要的基因的能力而闻名。然而，VDR 的活性广泛而复杂，因为它也因其抗增殖特性而闻名，并且正在与细胞毒性药物联合用于癌症治疗进行测试。我们发现，在用 DNA 损伤剂处理的细胞中，VDR 是形成 DNA 损伤灶所必需的。因此，缺乏 VDR 的细胞的化学敏化可能是由于促进细胞存活的 DNA 损伤反应被破坏所致。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。姜黄素作为化学增敏剂的使用已有充分记录，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 发挥作用，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 p53 状态的背景，因此还将评估对姜黄素诱导的化学敏化的影响。我们的研究具有显着的临床影响，因为大部分胰腺肿瘤和细胞品系表达突变型p53。 p53 的状态可能决定是否使用维生素 D 类似物或拮抗剂和姜黄素以及标准化疗来治疗癌症患者。