Biointeractions of Antiestrogens with Nitric Oxide

抗雌激素与一氧化氮的生物相互作用

• 批准号: 8896479
• 负责人: Gregory R. J Thatcher
• 金额: $ 23.52万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896479
• 关键词: Adverse effects; Affinity; Agonist; Alkylation; Apoptosis; Attenuated; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Epithelial Cells; Cell Culture Techniques; Cell Line; Cell Nucleus; Cells; Characteristics; Chemicals; Clinical; DNA Adduction; DNA Adducts; DNA Damage; DNA Modification Process; Data; Deamination; Depurination; Development; Estrogen Antagonists; Estrogen Metabolism; Estrogen Receptor Modulators; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Foundations; Funding; Goals; Grant; Growth; Hormonal; Hormonal Carcinogenesis; Hormone replacement therapy; Human; In Vitro; Inbred ACI Rats; Libraries; Link; MCF10A cells; MCF7 cell; MDA MB 231; Malignant - descriptor; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Measurement; Measures; Menopausal Symptom; Modeling; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Nitrosation; Normal Cell; Nucleic Acids; Oxidation-Reduction; Pharmaceutical Preparations; Plasma; Post-Translational Protein Processing; Postmenopause; Prevention therapy; Process; Production; Property; Proteins; Quinones; Raloxifene; Receptor Cell; Reporting; Risk; Selective Estrogen Receptor Modulators; Structure; Syndrome; System; T47D; Tamoxifen; Techniques; Therapeutic; Therapeutic Agents; Time; Tissues; Tumor Promotion; Writing; adduct; attenuation; base; benzothiophene; cancer chemoprevention; cancer risk; carcinogenesis; chemical carcinogenesis; cytotoxic; design; expectation; improved; in vivo; malignant breast neoplasm; novel; oxidation; oxidative DNA damage; receptor; research study; response; risk benefit ratio; sensor; therapy development; tumor; tumor initiation; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Use of estrogen/hormone replacement therapy (HRT) for post-menopausal symptoms has plummeted because of increased breast cancer risk associated with hormonal and chemical carcinogenesis. Selective estrogen receptor modulators (SERMs) could provide an alternative to HRT, but development has stalled because of the risk of side effects including carcinogenesis. The benzothiophene SERM (BT-SERM) raloxifene is currently the sole SERM in clinical use for postmenopausal syndrome and breast cancer chemoprevention. SERMs act as estrogen agonists in some tissues and both estrogens and SERMs are oxidatively metabolized to electrophilic quinones with potential to generate ROS. Estrogen agonists have been shown to elevate cellular NO; NO is implicated in breast cancer tumorigenesis. Quinones, ROS, and NO can interact chemically and also modify proteins and damage DNA. This proposal is directed at understanding how estrogen-dependent carcinogenesis can be attenuated by NO modulation and by appropriately designed SERMs that are redox-active but not themselves carcinogenic, to provide a basis for design of safe, non-carcinogenic SERMs for HRT and beyond. In Aim 1, new BT-SERMs will be synthesized and profiled as cellular probes. In vitro DNA damage and protein modification will be studied by LC-MS/MS. This aim will determine the protein and nucleic acid adducts of the chemical interaction with quinones, NO, and ROS generated by (anti)estrogens, and the influence of quinone structure on these products, allowing comparison with Aim 2 results in cell cultures. Aim 2 will study modulation of oxidative DNA damage in mammary cell cultures leading to apoptosis or malignant transformation. We hypothesize that malignant transformation of breast cancer cells reflects estrogen chemical carcinogenesis and therefore will be predictive for BT-SERM and NO modulating treatments that will attenuate tumorigenesis in experiments planned in Aim 3. In Aim 3, the ACI rat, an established model for estrogen-induced mammary carcinogenesis will be used to study the effect of one BT-SERM and NO modulation on carcinogenesis and tumor regression.

描述（由申请人提供）：由于与激素和化学致癌作用相关的乳腺癌风险增加，使用雌激素/激素替代疗法（HRT）治疗绝经后症状已大幅下降。选择性雌激素受体调节剂（SERM）可以提供替代HRT的方法，但由于副作用（包括致癌作用）的风险，开发已经停滞。苯并噻吩SERM（BT-SERM）雷洛昔芬是目前临床上唯一用于绝经后综合征和乳腺癌化学预防的SERM。SERM在某些组织中作为雌激素激动剂，雌激素和SERM都被氧化代谢为具有产生ROS潜力的亲电子醌。雌激素激动剂已被证明可以提高细胞NO; NO与乳腺癌肿瘤发生有关。醌、ROS和NO可以化学相互作用，也可以修饰蛋白质和损伤DNA。这项建议是针对了解如何雌激素依赖性致癌作用可以通过NO调节和适当设计的SERM，是氧化还原活性，但本身不致癌，为HRT和超越安全，非致癌SERM的设计提供了基础。在目标1中，将合成新的BT-SERM并将其作为细胞探针进行分析。体外DNA损伤和蛋白质修饰将通过LC-MS/MS进行研究。这一目的将确定与醌，NO和ROS产生的（抗）雌激素的化学相互作用的蛋白质和核酸加合物，以及醌结构对这些产品的影响，允许与细胞培养中的目标2结果进行比较。目的2研究乳腺细胞培养中氧化性DNA损伤导致细胞凋亡或恶性转化的调控。我们假设乳腺癌细胞的恶性转化反映了雌激素化学致癌作用，因此将预测BT-SERM和NO调节治疗，这将在目标3中计划的实验中减弱肿瘤发生。在目的3中，ACI大鼠，一种已建立的雌激素诱导的乳腺癌发生模型，将用于研究BT-SERM和NO调节对癌发生和肿瘤消退的影响。

项目成果

Selective estrogen receptor modulator delivery of quinone warheads to DNA triggering apoptosis in breast cancer cells.

• DOI: 10.1021/cb9001848
• 发表时间: 2009-12-18
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Peng, Kuan-wei;Wang, Huali;Qin, Zhihui;Wijewickrama, Gihani T.;Lu, Meiling;Wang, Zhican;Bolton, Judy L.;Thatcher, Gregory R. J.
• 通讯作者: Thatcher, Gregory R. J.

Quinone-induced activation of Keap1/Nrf2 signaling by aspirin prodrugs masquerading as nitric oxide.

• DOI: 10.1021/tx3003609
• 发表时间: 2012-12-17
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Dunlap T;Piyankarage SC;Wijewickrama GT;Abdul-Hay S;Vanni M;Litosh V;Luo J;Thatcher GR
• 通讯作者: Thatcher GR

Novel selective estrogen mimics for the treatment of tamoxifen-resistant breast cancer.

• DOI: 10.1158/1535-7163.mct-14-0319
• 发表时间: 2014-11
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Molloy ME;White BE;Gherezghiher T;Michalsen BT;Xiong R;Patel H;Zhao H;Maximov PY;Jordan VC;Thatcher GR;Tonetti DA
• 通讯作者: Tonetti DA

Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism.

• DOI: 10.1021/cn100106a
• 发表时间: 2011-05-18
• 期刊: ACS CHEMICAL NEUROSCIENCE
• 影响因子: 5
• 作者: Abdelhamid, Ramy;Luo, Jia;VandeVrede, Lawren;Kundu, Indraneel;Michalsen, Bradley;Litosh, Vladislav A.;Schiefer, Isaac T.;Gherezghiher, Teshome;Yao, Ping;Qin, Zhihui;Thatcher, Gregory R. J.
• 通讯作者: Thatcher, Gregory R. J.

Proteomic profiling of nitrosative stress: protein S-oxidation accompanies S-nitrosylation.

亚硝化应激的蛋白质组学分析：蛋白质 S-氧化伴随 S-亚硝基化。

• DOI: 10.1021/cb400547u
• 发表时间: 2014
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Wang,Yue-Ting;Piyankarage,SujeewaC;Williams,DavidL;Thatcher,GregoryRJ
• 通讯作者: Thatcher,GregoryRJ