EFFECTS OF FLEX-HETS ON CANCER CELL METABOLISM: NADH OXIDOREDUCTASE INHIBITION

Flex-HETS 对癌细胞代谢的影响：NADH 氧化还原酶抑制

• 批准号: 7960035
• 负责人: KELLY J WILLIAM
• 金额: $ 7.62万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960035
• 关键词: Affect; Apoptosis; Biological Assay; Biomedical Research; Cancerous; Capsaicin; Cell Respiration; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytochromes; Dose; Electron Transport; Enzyme Kinetics; Funding; Generations; Grant; Heteroarotinoids; Inhibitory Concentration 50; Institution; Lead; Membrane; Metabolism; Mitochondria; NADH oxidoreductase; Neoplasms; Normal Cell; Oklahoma; Ovarian; Play; Prevention; Research; Research Personnel; Resources; Respiration; Retinoids; Role; Rotenone; SHetA2; Source; Structure; System; Tetrahydronaphthalenes; United States National Institutes of Health; cancer cell; cancer therapy; density; flexibility; inhibitor/antagonist; novel; particle

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Flex-Hets, novel classes of conformationally flexible synthetic retinoid that include heteroatoms (O or S) incorporated within the tetrahydronaphthalene structure show great potential in the prevention and treatment of cancer. Flex-Hets induce apoptosis and demonstrate considerably more activity against cancer cells than normal cells. We have observed rapid effects of Flex-Hets on mitochondrial density, membrane integrity, Cytochrome C release, ROS generation and caspace activation, all indicative of the intrinsic apoptosis pathway, in treated A2780 cancer cells. Mitochondria play critical roles in cellular oxidative metabolism through an electron transport system located in their inner membrane. Known inhibitors of mitochondrial NADH oxidoreductase (Complex I) induce apoptosis and increase ROS in a variety of neoplasm. Flex-Hets may represent a new structural class of compounds that induce apoptosis through inhibition of mitochondrial electron transport. Preliminary results from our lab have demonstrated that the lead Flex-Het, SHetA2, inhibits mitochondrial Complex I activity and mitochondrial respiration in a dose dependent manner. However, the exact mechanism of inhibition is not clearly understood. Our aim is to categorize the mechanism of Complex I inhibition by FlexHets in sub mitochondrial particles isolated from both cancerous and normal ovarian cells. We will then carry out stead state enzyme kinetic assays to determine the Vmax, km and IC50 (concentration of inhibitor required to affect a 50% inhibition in complex I) of SHetA2 and several related heteroarotinoids compared to several of the know inhibitors such as piericidan A, rotenone or capsaicin.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Flex-hets是一类构象灵活的新型合成维甲酸，它包括四氢萘结构中的杂原子(O或S)，在预防和治疗癌症方面显示出巨大的潜力。FLEX-HETS可诱导细胞凋亡，并显示出比正常细胞更强的抗癌细胞活性。我们观察到Flex-HETS对经处理的A2780癌细胞的线粒体密度、膜完整性、细胞色素C释放、ROS生成和cspace激活的快速影响，所有这些都表明了内在的凋亡途径。线粒体通过位于其内膜的电子传递系统在细胞氧化代谢中发挥关键作用。已知的线粒体NADH氧化还原酶抑制剂(复合体I)在多种肿瘤中诱导细胞凋亡和增加ROS。Flex-hets可能代表了一种新的结构类型的化合物，它通过抑制线粒体电子传递来诱导细胞凋亡。我们实验室的初步结果表明，铅Flex-Het SHetA2以剂量依赖的方式抑制线粒体复合体I的活性和线粒体的呼吸。然而，抑制的确切机制尚不清楚。我们的目的是对FlexHets抑制卵巢癌细胞和正常卵巢细胞线粒体亚颗粒中的复合体I的机制进行分类。然后，我们将进行稳态酶动力学分析，以确定SHetA2和几个相关的杂芳烃与已知的几种抑制剂(如Piericidan A、鱼藤酮或辣椒素)的Vmax、Km和IC50(影响复合体I 50%抑制所需的抑制剂浓度)。