Role of HIF-1 alpha in EcSOD-Induced Growth Inhibition of Pancreatic Cancer

HIF-1 α 在 EcSOD 诱导的胰腺癌生长抑制中的作用

• 批准号: 8624510
• 负责人: Joseph J Cullen
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624510
• 关键词: 5 year old; Address; Age; Antioxidants; Cancer Cell Growth; Cancer Etiology; Cancer cell line; Caring; Cessation of life; Chemicals; Clinical Trials; Data; Development; Diagnosis; Disease; Dominant-Negative Mutation; Drug Targeting; Enzymes; Erythropoiesis; Excision; Fluorouracil; Foundations; Gene Targeting; Glycolysis; Growth; HIF1A gene; Human; Hypoxia Inducible Factor; In Vitro; Incidence; Left; Life; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Medicine; Mission; Operative Surgical Procedures; Pancreatic Adenocarcinoma; Patient Care; Patients; Population; Pre-Clinical Model; Process; Procollagen-Proline Dioxygenase; Radiation therapy; Regimen; Reporting; Research; Role; Small Interfering RNA; Superoxide Dismutase; Superoxides; Testing; Therapeutic; Tumor Suppression; United States; Veterans; angiogenesis; cancer cell; cell growth; chemotherapeutic agent; chemotherapy; combined cancer modality therapy; design; effective therapy; expression vector; extracellular; gemcitabine; improved; in vivo; inhibitor/antagonist; malignant phenotype; neoplastic cell; novel; overexpression; pancreatic cancer cells; programs; public health relevance; standard of care; tempol; therapeutic target; transcription factor; treatment strategy; tumor

DESCRIPTION (provided by applicant): Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence. Because of the poor therapeutic responsiveness of pancreatic cancer to surgery, chemotherapy, and radiation therapy, survival beyond five years is rare with median survival less than six months. Thus, novel and effective therapies directed against pancreatic cancer are needed to control progression and metastatic disease. Our studies have shown that scavenging superoxide with the antioxidant enzyme extracellular superoxide dismutase (EcSOD) or pharmacologically with the nitroxide compound tempol, have a strong tumor-suppressive effect in pancreatic cancer both in vitro and in vivo. New data presented in this proposal shows that overexpression of EcSOD leads to suppression of hypoxia inducible factor- 1a (HIF-1a). HIF-1a responds to reduced O2 availability by regulating crucial homeostatic processes such as angiogenesis, glycolysis, and erythropoiesis and has been suggested to be an important regulator of pancreatic cancer cell progression and survival. As a transcription factor, HIF-1 has more than 80 known target genes and the number continues 1. Determine whether the effects of EcSOD overexpression on pancreatic cancer cell growth inhibition are due to HIF-1a suppression by manipulating HIF-1a levels genetically and pharmaceutically. to increase. The current proposal will test the hypothesis that themechanism for the tumor suppressive effect of EcSOD and/or tempol is caused inlarge part due to the suppression of HIF-1 in pancreatic cancer and that this suppression is due to the removal of superoxide. In order to examine this hypothesis, we will address the following three Specific Aims: 2. Determine if pharmacological scavenging of superoxide in human pancreatic cancer cells with Tempol mimics the effects observed with EcSOD on HIF-1a. 3. Determine if Tempol-induced growth inhibition can be enhanced by chemotherapeutic agents (gemcitabine, 5-FU) in human pancreatic cancer. As reported in a recent NCI cancer bulletin article on pancreatic cancer, ¿the slow but steady march toward more individualized care in cancer medicine has left pancreatic cancer behind. Patients diagnosed with this disease live no longer today than patients diagnosed two decades ago, despite more than a dozen large clinical trials. Even as many patients with other cancers have benefited from targeted drugs, pancreatic cancer remains as deadly as ever¿ (http://www.cancer.gov/ncicancerbulletin/110309/page1). If we can rigorously demonstrate that the tumor suppressive effect of EcSOD and/or tempol is caused in large part by the suppression of HIF-1 in pancreatic cancer then the results of this proposed research program will provide a foundation for the rational design of a combined modality cancer therapy.

描述（由申请人提供）： 胰腺腺癌是美国癌症死亡的第四大原因，并且发病率正在上升，因为胰腺癌对手术、化疗和放射治疗的治疗反应较差，超过五年的生存期很少，中位生存期也较低。因此，需要针对胰腺癌的新型有效疗法来控制进展和转移性疾病，用抗氧化酶细胞外超氧化物歧化酶（EcSOD）或药物清除超氧化物。硝基氧化合物 tempol 在体外和体内对胰腺癌都有很强的肿瘤抑制作用，该提案中提出的新数据表明，EcSOD 的过度表达会抑制缺氧诱导因子 - 1a (HIF-1a) 的反应。通过调节重要的稳态过程（如血管生成、糖酵解和红细胞生成）来减少 O2 的可用性，并被认为是作为一种转录因子，HIF-1 具有 80 多个已知靶基因，并且数量还在持续增加。 1. 通过操纵 HIF-1a 抑制，确定 EcSOD 过表达对胰腺癌细胞生长抑制的影响是否是由于 HIF-1a 抑制所致。 HIF-1a 水平在遗传和药学上增加，目前的提议将检验 EcSOD 和/或 tempol 的肿瘤抑制作用的机制很大程度上是由于这一假设。胰腺癌中 HIF-1 的抑制，并且这种抑制是由于超氧化物的去除所致。为了检验这一假设，我们将解决以下三个具体目标： 2. 确定人胰腺癌细胞中超氧化物是否具有药物清除作用。使用 Tempol 模拟了使用 EcSOD 对 HIF-1a 观察到的效果。 3. 确定化疗药物（吉西他滨、吉西他滨、吉西他滨）是否可以增强 Tempol 诱导的生长抑制作用。 5-FU）在人类胰腺癌中的作用正如最近 NCI 癌症通报文章中关于胰腺癌的报道，¿尽管进行了十多项大型临床试验，但癌症医学向更加个性化的治疗缓慢而稳定的发展使得如今诊断出的胰腺癌患者的寿命并不比二十年前诊断的患者要长。尽管受益于靶向药物，胰腺癌仍然像以前一样致命。 (http://www.cancer.gov/ncicancerbulletin/110309/page1) 如果我们能够严格证明 EcSOD 和/或 tempol 的肿瘤抑制作用很大程度上是由抑制胰腺癌中的 HIF-1 引起的。该拟议研究计划的结果将为合理设计癌症联合疗法奠定基础。