权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of dihydroartemisinin as a novel preventive agent for prostate cancer

双氢青蒿素作为前列腺癌新型预防剂的开发

基本信息

批准号：
8242022
负责人：
M. SAEED SHEIKH
金额：
$ 7.98万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242022
关键词：
Adenocarcinoma Affect Age American Animal Model Animals Antimalarials Antineoplastic Agents Apoptosis Apoptotic Artemisia annua Artemisinins Binding Sites Biochemical Cause of Death Cells Chemoprevention Chemopreventive Agent Chinese Traditional Medicine Clinic Coupled DU145 Death Receptor 5 Development Disease Elderly Exhibits Genes Human Incidence LNCaP Lesion Ligands Link Lung Malaria Malignant Neoplasms Malignant neoplasm of prostate Mediating Messenger RNA Metastatic Neoplasm to Lymph Nodes Molecular Mus Mutant Strains Mice NKX3-1 gene Neoplasm Metastasis Outcome Study Pharmaceutical Preparations Phenotype Pilot Projects Plant Extracts Plants Prevention strategy Preventive Promoter Regions Prostate Adenocarcinoma Prostatic Neoplasms Proteins Proto-Oncogene Proteins c-akt Quality of life Role Signal Transduction TNFSF10 gene Testing Therapeutic Tumor Suppressor Proteins Up-Regulation artemisinine base cancer cell cancer chemoprevention cell growth combinatorial fight against homeodomain human disease improved insight men novel promoter prostate cancer prevention prostate carcinogenesis public health relevance transcription factor

项目摘要

DESCRIPTION (provided by applicant): Dihydroartemisinin (DHA) is an active metabolite of artemisinin. Artemisinin was first identified and extracted from traditional Chinese medicine qinghao (plant Artemisia annua L) in 1972. DHA has been extensively used in the clinic to treat malaria and is well-tolerated by humans and animals. In our preliminary studies, we have found that DHA induces apoptosis in human prostate cancer cells. We have also found that DHA upregulates death receptor 5 (DR5) and cooperates with TRAIL (the ligand for DR5 that has potentially emerged as a novel nontoxic anticancer agent) to induce apoptosis in human prostate cancer cells. Furthermore, DHA strongly inhibits Akt (protein kinase B), which is a key player in transducing survival signals. NKX3.1 is a homeodomain transcription factor and its function is linked to inhibition of prostate carcinogenesis. Our preliminary results also indicate that NKX3.1 upregulates DR5 promoter function. Therefore, we hypothesize that the anti-malarial drug DHA has a significant potential for prevention of prostate cancer. Our preliminary results support our hypothesis and form the basis of this application to further study the molecular mechanisms by which DHA mediates its anticancer effect and to develop this agent as a novel cancer-preventive agent for prostate cancer. We are proposing two specific aims to test our hypothesis. Specific Aim 1 is to investigate the role of homeodomain NKX3.1 transcription factor in mediating DHA-induced upregulation of DR5. Specific Aim 2 is to investigate the prostate cancer preventive effects of DHA in TRAMP and Nkx3.1/Pten mutant mice. These are pilot studies and if successful, will (i) provide important insights into the molecular mechanisms by which DHA mediates its apoptotic and anticancer effects and (ii) lay the groundwork to develop DHA as a novel cancer-preventive agent for prostate cancer.

描述(由申请人提供)：双氢青蒿素(DHA)是青蒿素的活性代谢物。青蒿素于1972年首次从中药材青蒿素(青蒿素、青蒿DHA在临床上已被广泛用于治疗疟疾，并被人和动物耐受性良好。在我们的初步研究中，我们发现DHA诱导人前列腺癌细胞凋亡。我们还发现，DHA上调死亡受体5(DR5)，并与TRAIL(DR5的配体，潜在地成为一种新的无毒抗癌药物)合作诱导人前列腺癌细胞凋亡。此外，DHA强烈抑制Akt(蛋白激酶B)，Akt是传递生存信号的关键角色。NKX3.1是一种同源结构域转录因子，其功能与抑制前列腺癌的发生有关。我们的初步结果还表明，NKX3.1上调了DR5启动子的功能。因此，我们假设抗疟疾药物DHA在预防前列腺癌方面有很大的潜力。我们的初步结果支持了我们的假说，并为进一步研究DHA介导其抗癌作用的分子机制以及开发该药物作为前列腺癌的新型防癌药物奠定了基础。我们提出了两个具体目标来检验我们的假设。具体目的1是研究同源结构域NKX3.1转录因子在DHA诱导的DR5上调中的作用。目的2研究DHA对TRAMP和Nkx3.1/Pten突变小鼠前列腺癌的预防作用。这些是试验性研究，如果成功，将(I)为DHA介导其凋亡和抗癌作用的分子机制提供重要的见解，并(Ii)为将DHA开发为一种新型前列腺癌防癌药物奠定基础。