HIF and Anticancer Drug Action

HIF 与抗癌药物作用

• 批准号: 7088900
• 负责人: GARTH POWIS
• 金额: $ 46.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088900
• 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）： 缺氧癌细胞存在于所有实体瘤中，并且发生在肿瘤生长超过新血管形成的区域。缺氧的癌细胞对化疗和放疗具有抵抗力，是癌症治疗失败的主要原因。关于细胞对缺氧反应的细胞生物学的新知识提供了令人兴奋的新方法来攻击缺氧癌细胞并利用其独特的生物学进行选择性治疗。细胞对缺氧的反应是由 HIF-1 转录因子介导的，HIF-1 是一种由缺氧诱导型 HIF-.1 亚基和组成型 HIF-1 组成的异二聚体。亚基。 HIF-1 诱导的基因使癌细胞能够使其代谢适应恶劣的厌氧环境，对程序性细胞死亡（细胞凋亡）产生抵抗力，并转移到新的低氧环境。 HIF-1 还诱导一系列细胞因子的产生，包括血管内皮生长因子 (VEGF)，促进现有血管形成新的肿瘤毛细血管（血管生成）。我们提供的证据表明，缺氧诱导癌细胞中 HIF-1 增加的一个必要因素是氧化还原蛋白硫氧还蛋白-1 (Trx-1)。 Trx-1 表达在许多人类原发性肿瘤中增加，与侵袭性肿瘤生长和患者生存率降低相关。我们发现，Trx-1 的增加会导致缺氧诱导的 HIF-.1 水平和 HIF-1 反式激活活性增加，缺氧诱导的基因（如 VEGF）的表达增加，并导致肿瘤血管生成增加。我们的工作所基于的假设是，通过氧化还原机制，Trx-1 对于缺氧诱导的 HIF-.1 增加及其随后对肿瘤生长和血管生成增加的影响是必需的。我们还提出，抑制 HIF 氧化还原控制的药物将剥夺癌细胞的缺氧优势，并提供一种新颖且有效的癌症治疗方法。我们已确定侧耳素是第一种新型 HIF-.1 抑制性抗肿瘤药物，其通过抑制硫氧还蛋白还原酶发挥作用，从而逆转 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 的氧化还原调节和侧耳素对 HIF-.1 的抑制进行机制研究。