STRUCTURAL ANALYSIS OF COPPER-CONTAINING COMPLEXES IN SOLUTION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 两条研究线表明，铜（Cu）是癌症治疗的一种新的选择性靶点。(i)Cu对于肿瘤血管生成是必需的，并且在许多类型的人类癌症中发现高水平的Cu。(ii)在正常器官中（例如，肝脏），当铜的生物利用度降低至基线的80%时，没有观察到已知的有害影响。最近的研究也表明蛋白酶体抑制剂作为潜在的新型抗癌药物的用途。几种铜结合化合物，包括抗生素氯碘羟喹、抗酒精中毒药物双硫仑（DSF）和抗HIV药物二乙基二硫代氨基甲酸酯（DDTC，DSF的代谢物），具有抗细菌、抗真菌和/或抗HIV活性。DSF和DDTC已分别被FDA批准用于治疗酒精中毒和HIV。临床试验表明，这些药物的疗效无毒性。这些药物是否具有抗肿瘤活性尚未得到证实。我们已经发现DSF-Cu和DDTC-Cu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的BioCAT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Cu结合，形成具有蛋白酶体抑制和细胞杀伤活性的特异性复合物。我们与Barrea博士一起计划了实验，并考虑了潜在的问题。我们认为，所产生的数据对于编写若干共同出版物和提案极为重要。

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.