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

描述(由申请人提供)： 在美国，胰腺癌是导致癌症死亡的第四大原因，而且发病率正在上升。由于胰腺癌对手术、化疗和放射治疗的治疗反应性很差，超过五年的生存期很少，中位生存期不到六个月。因此，需要针对胰腺癌的新的有效的治疗方法来控制疾病的进展和转移。我们的研究表明，无论是用抗氧化剂细胞外超氧化物歧化酶(EcSOD)清除超氧化物歧化酶(EcSOD)，还是用氮氧化物化合物Tempoll药理作用，在体内外都对胰腺癌有很强的抑瘤作用。这项提案中提出的新数据表明，EcSOD的过表达导致低氧诱导因子-1a(HIF-1a)的抑制。HIF-1a通过调节血管生成、糖酵解和红细胞生成等关键的动态平衡过程来应对氧气供应减少，并被认为是胰腺癌细胞进展和生存的重要调节因素。作为一种转录因子，HIF-1有80多个已知的靶基因，并且这个数字还在1。通过从基因和药物水平上调控HIF-1a的水平，确定EcSOD过表达对胰腺癌细胞生长抑制的影响是否由于HIF-1a的抑制。来增加。目前的建议将检验这一假说，即EcSOD和/或temol的抑瘤作用在很大程度上是由于胰腺癌中HIF-1的抑制，这种抑制是由于清除超氧化物。为了验证这一假设，我们将解决以下三个具体目标：2.确定Tempoll清除人胰腺癌细胞中超氧化物歧化酶的药理作用是否与EcSOD对HIF-1a的影响相似。3.确定化疗药物(吉西他滨、5-FU)能否增强坦普尔对人胰腺癌的生长抑制作用。正如最近NCI癌症公报中关于胰腺癌的一篇文章所报道的那样，癌症医学朝着更个性化的方向缓慢但稳步地前进，已经把胰腺癌抛在了后面。尽管进行了十几项大型临床试验，但被诊断患有这种疾病的患者今天的寿命并不比20年前诊断的患者更长。即使许多患有其他癌症的患者从靶向药物中受益，胰腺癌仍然一如既往地致命。[(http://www.cancer.gov/ncicancerbulletin/110309/page1).如果我们能严格地证明EcSOD和/或temol的抑瘤作用在很大程度上是通过抑制胰腺癌中的HIF-1而引起的，那么本研究计划的结果将为合理设计联合治疗方案提供基础。

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.