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：
8636411
负责人：
Timothy Yen
金额：
$ 22.6万
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/8636411
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）是美国癌症死亡的第四个主要原因，并具有最差的预后，预期寿命中位数不到一年。由于该疾病在后期被诊断出来，因此治疗方案受到限制。手术只能适度提高预期寿命。胰腺腺癌对常规化学疗法具有高度的耐热性。相对于辐射和紫杉醇，吉西他滨被认为是最有效的药物。然而，清醒的统计数据是，吉西他滨只会将患者的生存延长几个月，而不是其他疗法。由于与吉西他滨的联合疗法相遇有限，因此化学抗性的分子基础可能是高度复杂的。迫切需要确定提高胰腺癌细胞对化学疗法的敏感性的方法。在初步实验中，我们进行了全基因组siRNA筛选，以鉴定负责吉西他滨灵敏度的基因。我们确定了一小部分基因，其中包括维生素D受体（VDR）以及各种相关的相互作用和下游基因。我们已经验证了VDR是体外吉西他滨灵敏度的重要决定因素。使用独立的VDR siRNA，通过克隆生存确定的两种细胞系（PANC1和BXPC3）实现了吉西他滨的敏化。 VDR是一种核激素受体，其最著名的是其调节对钙稳态和骨骼矿化重要的基因的能力。然而，VDR的活性既广阔又复杂，因为它的抗增殖特性也闻名，并正在与细胞毒性剂结合进行癌症治疗。我们发现，在用DNA损伤剂处理的细胞中形成DNA受损灶是必需的。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损伤反应的破坏。该提议旨在扩大最近的发现，即天然复合姜黄素是VDR的配体。使用姜黄素作为化学敏化剂的使用有充分的文献证明，但其作用方式仍然晦涩难懂。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起作用以增强胰腺癌细胞的化学敏化。此外，由于已知VDR的细胞保护作用取决于突变体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，因为胰腺肿瘤和细胞很大一部分线表达突变体P53。 p53的状态可能决定是否治疗维生素D类似物或拮抗剂和姜黄素以及标准化学疗法的癌症患者。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Changing the selectivity of p300 by acetyl-CoA modulation of histone acetylation.

DOI：
10.1021/cb500726b
发表时间：
2015-01-16
期刊：
ACS CHEMICAL BIOLOGY
影响因子：
4
作者：
Henry, Ryan A.;Kuo, Yin-Ming;Bhattacharjee, Vikram;Yen, Timothy J.;Andrews, Andrew J.
通讯作者：
Andrews, Andrew J.