Hypoxia Inducible Factor and Anticancer Drug Action

缺氧诱导因子与抗癌药物作用

• 批准号: 6683375
• 负责人: GARTH POWIS
• 金额: $ 33.71万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6683375
• 关键词: MCF7 cell; NAD(P)H oxidoreductase; SCID mouse; angiogenesis; antineoplastics; biological signal transduction; doxorubicin; drug screening /evaluation; hypoxia; hypoxia inducible factor 1; immunocytochemistry; magnetic resonance imaging; neoplastic cell; neoplastic growth; oxidation reduction reaction; oxidoreductase inhibitor; protein structure function; thioredoxin; xenotransplantation

DESCRIPTION (provided by applicant): Hypoxic cancer ceils are found in all solid tumors and occur in regions where tumor growth outstrips new blood vessel formation. Hypoxic cancer cells are resistant to chemotherapy and radiation and are a major reason for the failure of cancer therapy. New knowledge of the cellular biology of the cell's response to hypoxia offers exciting new ways of attacking hypoxic cancer cells and exploiting their unique biology for selective therapy. The cells response to hypoxia is mediated by the HIF-1 transcription factor, a heterodimer composed of a hypoxia inducible HIF-.1 subunit and a constitutive HIF-1. subunit. Genes induced by HIF-1 allow the cancer cell to adapt its metabolism to the hostile anaerobic environment, to become resistant to programmed cell death (apoptosis) and to metastasize to new less hypoxic environments. HIF-1 also induces the production of a family of cytokines, including vascular endothelial growth factor (VEGF), that promote the formation of new tumor capillary blood vessels from pre-existing blood vessels (angiogenesis). We present evidence that a necessary factor for the hypoxia-induced increase in HIF-1 in cancer cells is the redox protein thioredoxin-1 (Trx-1). Trx-1 expression is increased in may human primary tumors where it is associated with aggressive tumor growth and decreased patient survival. We show that increased Trx-1 leads to increased hypoxia-induced HIF-.1 levels and HIF-1 transactivating activity, to increased expression of hypoxia induced genes such as VEGF and to increased tumor angiogenesis. The hypothesis upon which our work is based is that, acting by a redox mechanism, Trx-1 is necessary for the hypoxia-induced increase in HIF-.1 and its subsequent effects on tumor growth with increased angiogenesis. We also propose that drugs that inhibit the redox control of HIF.- will deprive the cancer cell of its hypoxic advantage and offer a novel and effective way of treating cancer. We have identified pleurotin as the first of a new class of HIF-.1 inhibitory antitumor agents that acts by inhibiting thioredoxin reductase, thus, reversing the redox effects of Trx-1 on HIF-.I. The objectives of our work are to conduct mechanistic studies of the redox regulation of HIF-.1 by Trx-1 and the inhibition of HIF-.1 by pleurotin.

描述（由申请人提供）： 在所有实体瘤中都发现了低氧癌天花板，并且发生在肿瘤生长量超过新血管形成的区域。低氧癌细胞对化学疗法和放射线有抵抗力，是癌症治疗失败的主要原因。对细胞对缺氧反应的细胞生物学的新知识为攻击低氧癌细胞并利用其独特的生物学进行选择性疗法提供了令人兴奋的新方法。细胞对缺氧的反应是由HIF-1转录因子介导的，HIF-1转录因子由缺氧诱导的HIF-.1亚基和组成型HIF-1组成。亚基。 HIF-1诱导的基因使癌细胞能够使其新陈代谢适应敌对的厌氧环境，使其对程序性细胞死亡（凋亡）具有抵抗力，并转移到新的低氧环境中。 HIF-1还诱导了包括血管内皮生长因子（VEGF）在内的一系列细胞因子的产生，该因子促进了先前存在的血管（血管生成）的新肿瘤毛细血管血管的形成。我们提供的证据表明，癌细胞中缺氧诱导的HIF-1增加的必要因素是氧化还原蛋白硫蛋白-1（TRX-1）。在5月的人类原发性肿瘤中，TRX-1表达与侵袭性肿瘤生长和患者生存降低有关。我们表明，TRX-1的增加导致缺氧诱导的HIF-.1水平和HIF-1反式激活活性增加，从而增加了缺氧诱导的基因（例如VEGF）的表达，并增加了肿瘤血管生成。我们工作所基于的假设是，通过氧化还原机制作用，TRX-1对于缺氧诱导的HIF-.1的增加及其随后对肿瘤生长的影响随血管生成的增加所必需。我们还建议抑制HIF的氧化还原控制的药物将剥夺癌细胞的低氧优势，并提供一种新颖有效的治疗癌症方法。我们已经确定胸膜素是通过抑制硫氧还蛋白还原酶起作用的新型HIF-.1抑制性抗肿瘤剂中的第一类，因此逆转了TRX-1对HIF-.i的氧化还原作用。我们工作的目标是对TRX-1对HIF-.1的氧化还原调节的机械研究以及胸膜素对HIF-.1的抑制作用。