STRUCTURAL ANALYSIS OF COPPER-CONTAINING COMPLEXES IN SOLUTION

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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.