Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to such unmet need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (Antabuse), an old alcohol-aversion drug effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify ditiocarb-copper complex as the metabolite of disulfiram responsible for anticancer effects, and provide methods to detect its preferential accumulation in tumours and candidate biomarkers for impact in cells and tissues. Finally, our functional and biophysical analyses reveal the long-sought molecular target of disulfiram’s tumour suppressing effects as NPL4, an adapter of p97/VCP segregase essential for protein turnover involved in multiple regulatory and stress-response cellular pathways.

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.

A series of three complexes with diethyldithiocarbamate ligand and three different metals (Ni, Cu, Zn) was prepared, confirmed by X-ray crystallography, and tested in human breast cancer MDA-MB-231 cells. Zinc and copper complexes, but not nickel complex, were found to be more active against cellular 26S proteasome than against purified 20S proteasome core particle. One of the possible explanations is inhibition of JAMM domain in the 19S proteasome lid.Since FDA approval of cisplatin 30 years ago, thousands of coordination compounds have been synthesized and screened. However, cisplatin and its analogues (carboplatin and oxali-platin), ranked among "alkylating agents", are the only metal-based anticancer drugs in common use. 1 Because many metal-based compounds are effective in vitro, 2 it is a great challenge to find an in vivo active metal drug sufficiently safe for clinical use. One of the promising strategies to accelerate drug discovery and development research seems to be in finding new uses for old drugs. Once approved, these drugs can quickly enter phase II clinical trials and save a lot of time and money. [3][4][5] Along that line, it deserves attention that an old anti-alcoholic drug disulfiram (tetraethylthiuram disulfide), in combination with zinc gluconate, has been reported to reduce hepatic metastases and produce clinical remission in a patient with ocular melanoma. 6 Furthermore, disulfiram mixed with copper was found to selectively destroy melanoma cells in vitro. 7 The antimelanoma activity of disulfiram was suggested to be attributed to diethyldithiocarbamate (EtDTC a ) complex with copper because disulfiram can be converted to EtDTC in the body. 8 Also, few other metal-dithiocarbamate complexes were shown to be effective against many types of cancer cells in vitro and in vivo. 9-13 However, the involved molecular mechanism has not been completely defined.The proteasome inhibition is a new and viable strategy in cancer therapy with the first-in-class approved drug bortezomib (dipeptide boronic acid analogue) as a successfule example. 14 A giant protease responsible for degradation of about 90% cellular proteins, the proteasome is * To whom correspondence should be addressed. Phone: 313-576-8301. Fax: 313-576-8307. E-mail: cvekb@seznam.cz (B.C.); doup@karmanos.org (Q.P.D.).Supporting Information Available: Basic information and reaction yields, crystal structure determination, crystal data and structure refinement, molecular structures of monomer complexes, molecular structure of dimers, inhibition of MBA-MD-231 cell line proliferation, apoptotic morphological changes in MBA-MD-231 cell line, proteasomal activity in intact cells, activity of purified 20S proteasome. This material is available free of charge via the Internet at http://pubs.acs.org. usually targeted at its proteolytically active β-rings (Figure 1). However, there is an increasing demand for new approaches to inhibit the proteasome, e.g., by targeting its so-called 19S particle ( Figure 1). 15 This component of the proteas...