Modulation of steroid sulfation by celecoxib-like drugs

塞来昔布类药物对类固醇硫酸化的调节

基本信息

批准号：
7587000
负责人：
Margaret Olive James
金额：
$ 7.33万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587000
关键词：
Allosteric Site Androgens Applications Grants Bile Acids Binding Biological Breast Breast Cancer Treatment Chemopreventive Agent Colon Carcinoma Crystallography Cytosol Degenerative polyarthritis Development Enzymes Estradiol Estrogens Ethinyl Estradiol Fishes Future Goals Grant Hepatocyte Human Human Volunteers Hydrolysis Hydroxyl Radical In Vitro Inorganic Sulfates Lead Liver Malignant neoplasm of lung Minor Molecular Organ Pathway interactions Pharmaceutical Preparations Positioning Attribute Prevention Preventive Prostaglandin-Endoperoxide Synthase Proteins Rate Rattus Recombinants Research Resistance Rheumatoid Arthritis Sheep Steroids Sulfatases Therapeutic Agents Therapeutic Effect Unspecified or Sulfate Ion Sulfates Woman Work cancer therapy celecoxib cyclooxygenase 1 cyclooxygenase 2 estradiol-3-sulfate in vivo inhibitor/antagonist interest malignant breast neoplasm monoamine-sulfating phenol sulfotransferase novel therapeutics steroid sulfotransferase sulfation sulfotransferase uptake

项目摘要

DESCRIPTION (provided by applicant): Evidence is mounting that the cyclo-oxygenase (COX) 2 inhibitor, celecoxib, a drug that is widely used to treat osteoarthritis and inflammatory arthritis, has chemo-preventive and chemo-therapeutic effects against breast cancer, colon cancer and lung cancer. As well as inhibiting COX-2, celecoxib interacts with sulfotransferases (SULT). Celecoxib stimulates the 17-sulfation and inhibits the 3-sulfation of estradiol catalyzed by human liver cytosol and by expressed recombinant human sulfotransferase 2A1 (hSULT2A1). Stimulation of 17-sulfation (normally a minor pathway) combined with inhibition of 3-sulfation (normally the major pathway) of estradiol and related estrogens should result in a reduction in the amount of active estrogen available to the breast. Estradiol-3-sulfate, but not 17-sulfate, is a transport form of estradiol that is taken up by the breast where it is hydrolyzed to estradiol. This effect should be beneficial for estrogen- sensitive breast cancers by reducing the uptake of estrogen into the breast. The long-term objective of this research is to ascertain the significance of the effect of celecoxib in modulating sulfation, with respect to its anticarcinogenic activity. This could lead to the development of new therapeutic agents for prevention or treatment of cancer. This small grant application is focused on defining the effect and determining the mechanism. The first specific aim is to examine the structural features of hSULT2A1 substrates, estrogens, androgens and bile acids that make them susceptible to the effect of celecoxib on sulfate conjugation. As well as hSULT2A1, human liver cytosol and expressed recombinant hSULT1A1 and 1E1 will be studied for the effect of celecoxib on their activity. The second specific aim is to study the protein crystallography of hSULT2A1 in the presence and absence of estradiol and celecoxib, so as to ascertain the molecular interaction of the substrate (estradiol) and modulator (celecoxib) with hSULT2A1, with the objective of gaining information on the structural features of celecoxib that induce this change in hSULT2A1 activity. Future research will determine if this in vitro defined effect occurs in human volunteers, and examine molecules related to celecoxib for their interaction with hSULT2A1

描述（由申请人提供）：有证据表明，环氧酶（COX）2抑制剂Celecoxib是一种广泛用于治疗骨关节炎和炎症性关节炎的药物，具有化学预防和化学治疗效果，针对乳腺癌，结肠癌和肺癌。除了抑制COX-2，Celecoxib还与硫代转移酶（SULT）相互作用。塞来昔布刺激17-硫化并抑制由人肝细胞质催化的雌二醇和通过表达的重组人磺胺硫代硫代酶2A1（HSULT2A1）催化的3-硫酸。刺激17-硫化（通常是次要途径），结合雌二醇和相关雌激素的3-硫化（通常是主要途径）的抑制作用，应导致乳腺可用的活性雌激素量减少。雌二醇-3-硫酸盐，但不是17-硫酸盐，是一种雌二醇的转运形式，被乳腺癌吸收到雌二醇中。这种作用应通过减少雌激素摄取乳房的摄取来对雌激素敏感的乳腺癌有益。这项研究的长期目的是确定塞来昔布在调节硫酸化的抗癌活性方面的作用。这可能导致开发用于预防或治疗癌症的新治疗剂。这个小的赠款应用集中在定义效果和确定机制上。第一个具体目的是检查HSULT2A1底物，雌激素，雄激素和胆汁酸的结构特征，这些特征使它们容易受到塞来昔布对硫酸盐结合的影响。以及HSULT2A1，还将研究人肝细胞质和表达的重组HSULT1A1和1E1，以实现塞来昔布对其活性的影响。第二个具体目的是研究在存在和不存在雌二醇和塞来昔布的情况下HSULT2A1的蛋白质晶体学，以确定底物（雌二醇）和调节剂（Celecoxib）与HSULT2A1的分子相互作用，并具有有关获得有关获得有关获得有关信息的目的Celecoxib的结构特征诱导了HSULT2A1活性的这种变化。未来的研究将确定这种体外定义效应是否发生在人类志愿者中，并检查与塞来昔布有关的分子与HSULT2A1相互作用