STRUCTURAL ANALYSIS OF COPPER-CONTAINING COMPLEXES IN SOLUTION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。两项研究表明，铜(Cu)是癌症治疗的一个新的、选择性的靶点。(I)铜对肿瘤血管生成是必不可少的，在许多类型的人类癌症中都发现了高水平的铜。(Ii)在人类和哺乳动物的正常器官(例如肝脏)中，当铜的生物利用率降低到基线的80%时，没有观察到已知的有害影响。最近的研究还表明，蛋白酶体抑制剂可能成为潜在的新型抗癌药物。几种铜结合化合物，包括抗生素CLOQONOL、抗酒精中毒药物DSF(DSF)和抗HIV药物二乙基二硫代氨基甲酸酯(DDTC)，具有抗细菌、抗真菌和/或抗HIV活性。DSF和DDTC已被FDA批准分别用于治疗酒精中毒和HIV。临床试验表明，这些药物的疗效是无毒性的。这些药物是否具有抗肿瘤活性尚未得到证实。我们发现DSF-铜和DDTC-铜化合物是人癌细胞中的蛋白酶体抑制剂和凋亡诱导剂。我们一直在与阿贡国家实验室APS生物CAT副主任Raul Barrea博士合作，使用同步辐射来验证有机配体(例如DSF或DDTC)可以与肿瘤细胞铜结合的新概念，形成具有蛋白酶体抑制和细胞杀伤活性的特定络合物。我们与巴雷亚博士一起，在考虑到潜在问题的情况下，计划了这项实验。我们认为，将产生的数据对几份联合出版物和提案的编写极为重要。

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. Two lines of research suggest that copper (Cu) is a novel, selective target for cancer therapies. (i) Cu is essential for tumor angiogenesis and high levels of Cu are found in many types of human cancers. (ii) In normal organs (e.g., liver) of humans and mammals, there are no known harmful effects observed when the bioavailability of Cu is decreased up to 80% of baseline. Recent research also suggests the use of proteasome inhibitors as potential novel anticancer drugs. Several Cu-binding compounds, including the antibiotics clioquinol, the anti-alcoholism drug Disulfiram (DSF), and the anti-HIV drug diethyldithiocarbamate (DDTC, a metabolite of DSF), have anti-bacteria, anti-fungi and/or anti-HIV activities. DSF and DDTC have been approved by the FDA for treatment of the alcoholism and HIV, respectively. Clinical trials have shown the efficacy of these drugs with no toxicity. Whether these drugs have anti-tumor activities has not been shown. We have found that DSF-Cu and DDTC-Cu compounds are proteasome inhibitors and apoptosis inducers in human cancer cells. We have been collaborating with Dr. Raul Barrea, Associate Director of BioCAT at APS, Argonne National Laboratory to use synchrotron radiation to verify the new concept that an organic ligand (e.g., DSF or DDTC) can bind with tumor cellular Cu, forming a specific complex with proteasome-inhibitory and cell-killing activities. Together with Dr. Barrea, we have planned the experiment included with consideration of potential problems. We believe that the data to be generated are extremely important for preparation of several co-publications and proposals.