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Oxidative Pentose Cycle in Hypoxic Cancer Cell Response

缺氧癌细胞反应中的氧化戊糖循环

基本信息

批准号：
7356449
负责人：
IRAIMOUDI S AYENE
金额：
$ 24.59万
依托单位：
LANKENAU INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7356449
关键词：
ABCC1 gene Affect Animals Antibodies Apoptotic Biochemical Biological Assay Breast Cell Death Cells Chemicals Chinese Hamster Ovary Cell Clinical Clinical Research Colon Complementary DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Repair Inhibition DNA repair protein DNA strand break Dose Double Strand Break Repair Doxorubicin/Etoposide Drug Efflux Drug Metabolic Detoxication Drug resistance Enzymes Exhibits G6PD gene Gamma Rays Gene Expression Genus Cola Glucose Glucosephosphate Dehydrogenase Glutathione Glycoproteins Guanine + Cytosine Composition HCT116 Cells High Pressure Liquid Chromatography Human Hypoxia Immunoglobulin Fragments In Vitro Ku Protein Lead Malignant neoplasm of prostate Mediating Metabolic Mitotic Modification Molecular Multidrug Resistance Associated Protein 1 NADP Neoplasm Metastasis Normal Cell Nucleotides Outcome Oxidants Oxidation-Reduction P-Glycoprotein P-Glycoproteins Pentose Phosphate Cycle Pathway Pentoses Play Principal Investigator Property Proteins Pulsed-Field Gel Electrophoresis Radiation Radiation induced damage Rate Rattus Resistance Rodent Role Second Primary Cancers Small Interfering RNA Solid Neoplasm Sulfhydryl Compounds Technology Testing Therapeutic Time Topoisomerase II Topoisomerase-II Inhibitor Toxic effect Vascularization antitumor agent cancer cell dehydroepiandrosterone deprivation expression vector functional loss improved in vivo inhibitor/antagonist inorganic phosphate mutant neoplastic cell oxidation programs protein function radiation resistance repaired response therapy outcome tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The role of hypoxia in the resistance of cancer cells to DNA damaging agents has been clearly demonstrated in in vitro and in vivo. Several clinical studies have also demonstrated poor therapeutic outcome for hypoxic tumors. DNA repair, repair protein Kf, and intracellular GSH detoxification play a major role in cellular response to DNA damaging topoisomerase II inhibitors and gamma radiation. Although the functions of these factors can be inhibited by oxidation of functional thiols, cells resist thiol redox changes by producing NADPH through oxidative pentose phosphate cycle (OPPC). For example hydroxyethyldisulfide (HEDS), a unique non-toxic thiol oxidant, is not effective in modifying the cellular thiol redox in normal CHO cells with OPPC. Our preliminary studies indicated, for the first time, that CHO mutants impaired with OPPC activity are the ideal candidates for HEDS-mediated sensitization to DNA damaging agents. This unique property of OPPC, which eliminates HEDS-mediated thiol redox modification and DNA damage sensitization, will be exploited to sensitize hypoxic cancer cells deprived of glucose, a substrate for OPPC, without affecting glucose proficient normal cells. Glucose deprivation is common in hypoxic cells of several solid tumors because of poor vascularization and higher metabolic activity. We hypothesize that glucose/OPPC depleted hypoxic cancer cells are susceptible to HEDS-mediated redox [Protein thiol (PSH) & glutathione (GSH)] modification and sensitization to "and tumor and DNA damaging" Topo II inhibitors and gamma radiation through multiple mechanisms that include inhibition of DNA repair, DNA repair protein function, GSH detoxification, and anti-apoptotic factors. We will test our hypothesis in hypoxic human cancer cells using biochemical and molecular approaches. First, we will determine the application of thiol redox modification in the sensitization of glucose deprived hypoxic cancer cells to topo II inhibitors and gamma radiation. Additional studies will also be conducted to test the efficacy of HEDS in low glucose hypoxic tumor in in vivo. Second, using siRNA and antibody technologies, we will determine whether specific inhibitors of OPPC can also induce HEDS-mediated redox modification, and subsequent sensitization of hypoxic cancer cells to DNA damaging agents. Finally, we will determine the mechanisms of redox modification- mediated hypoxic sensitization by determining its effect on DNA double strand breaks, DNA repair protein Kf, GSH detoxification and pro-apoptotic factors.

描述（由申请人提供）：缺氧在癌细胞对DNA损伤剂的抗性中的作用已在体外和体内得到明确证明。几项临床研究也证明了缺氧肿瘤的治疗效果较差。DNA修复、修复蛋白Kf和细胞内GSH解毒在细胞对DNA损伤拓扑异构酶II抑制剂和γ辐射的反应中起主要作用。虽然这些因子的功能可以被功能性硫醇的氧化抑制，但细胞通过氧化戊糖磷酸循环（OPPC）产生NADPH来抵抗硫醇的氧化还原变化。例如，羟乙基二硫化物（HEDS），一种独特的无毒硫醇氧化剂，在用OPPC修饰正常CHO细胞中的细胞硫醇氧化还原中无效。我们的初步研究表明，第一次，CHO突变体与OPPC活性受损的HEDS介导的致敏DNA损伤剂的理想候选人。OPPC的这种独特性质消除了HEDS介导的巯基氧化还原修饰和DNA损伤敏化，将被用于敏化缺乏葡萄糖（OPPC的底物）的缺氧癌细胞，而不影响葡萄糖丰富的正常细胞。葡萄糖剥夺在几种实体瘤的缺氧细胞中是常见的，因为血管化不良和代谢活性较高。我们假设葡萄糖/OPPC耗尽的低氧癌细胞对HEDS介导的氧化还原[蛋白硫醇（PSH）和谷胱甘肽（GSH）]修饰敏感，并且通过多种机制对“和肿瘤和DNA损伤”Topo II抑制剂和γ辐射敏感，所述机制包括抑制DNA修复、DNA修复蛋白功能、GSH解毒和抗凋亡因子。我们将使用生物化学和分子方法在缺氧的人类癌细胞中测试我们的假设。首先，我们将确定巯基氧化还原修饰在葡萄糖剥夺缺氧癌细胞对拓扑异构酶II抑制剂和γ辐射的敏化中的应用。还将进行额外的研究以测试HEDS在体内低糖缺氧肿瘤中的功效。其次，使用siRNA和抗体技术，我们将确定OPPC的特异性抑制剂是否也可以诱导HEDS介导的氧化还原修饰，以及随后的缺氧癌细胞对DNA损伤剂的敏感性。最后，我们将通过确定氧化还原修饰对DNA双链断裂、DNA修复蛋白Kf、GSH解毒和促凋亡因子的影响来确定氧化还原修饰介导的缺氧敏化的机制。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glucose deprivation increases nuclear DNA repair protein Ku and resistance to radiation induced oxidative stress in human cancer cells.

DOI：
10.1002/cbf.1541
发表时间：
2009-03
期刊：
CELL BIOCHEMISTRY AND FUNCTION
影响因子：
3.6
作者：
Li, Jie;Ayene, Roashan;Ward, Kathleen M.;Dayanandam, Eswarkumar;Ayene, Iraimoudi S.
通讯作者：
Ayene, Iraimoudi S.

Hydroxyethyl disulfide as an efficient metabolic assay for cell viability in vitro.

DOI：
10.1016/j.tiv.2012.01.007
发表时间：
2012-06
期刊：
TOXICOLOGY IN VITRO
影响因子：
3.2
作者：
Li, Jie;Zhang, Donglan;Ward, Kathleen M.;Prendergast, George C.;Ayene, Iraimoudi S.
通讯作者：
Ayene, Iraimoudi S.

A bioactive probe for glutathione-dependent antioxidant capacity in breast cancer patients: implications in measuring biological effects of arsenic compounds.

乳腺癌患者谷胱甘肽依赖性抗氧化能力的生物活性探针：测量砷化合物生物效应的意义。

DOI：
10.1016/j.vascn.2013.10.004
发表时间：
2014
期刊：
Journal of pharmacological and toxicological methods
影响因子：
1.9
作者：
Li,Jie;Zhang,Donglan;Jefferson,PearlA;Ward,KathleenM;Ayene,IraimoudiS
通讯作者：
Ayene,IraimoudiS

A bioactive probe of the oxidative pentose phosphate cycle: novel strategy to reverse radioresistance in glucose deprived human colon cancer cells.

氧化戊糖磷酸循环的生物活性探针：逆转葡萄糖剥夺的人结肠癌细胞放射抗性的新策略。

DOI：
10.1016/j.tiv.2012.08.012
发表时间：
2013
期刊：
Toxicology in vitro : an international journal published in association with BIBRA
影响因子：
0
作者：
Li,Jie;Ward,KathleenM;Zhang,Donglan;Dayanandam,Eswarkumar;Denittis,AlbertS;Prendergast,GeorgeC;Ayene,IraimoudiS
通讯作者：
Ayene,IraimoudiS