Despite several approved therapeutic modalities, multiple myeloma (MM) remains an incurable blood malignancy and only a small fraction of patients achieves prolonged disease control. The common anti-MM treatment targets proteasome with specific inhibitors (PI). The resulting interference with protein degradation is particularly toxic to MM cells as they typically accumulate large amounts of toxic proteins. However, MM cells often acquire resistance to PIs through aberrant expression or mutations of proteasome subunits such as PSMB5, resulting in disease recurrence and further treatment failure. Here we propose CuET-a proteasome-like inhibitor agent that is spontaneously formed in-vivo and in-vitro from the approved alcohol-abuse drug disulfiram (DSF), as a readily available treatment effective against diverse resistant forms of MM. We show that CuET efficiently kills also resistant MM cells adapted to proliferate under exposure to common anti-myeloma drugs such as bortezomib and carfilzomib used as the first-line therapy, as well as to other experimental drugs targeting protein degradation upstream of the proteasome. Furthermore, CuET can overcome also the adaptation mechanism based on reduced proteasome load, another clinically relevant form of treatment resistance. Data obtained from experimental treatment-resistant cellular models of human MM are further corroborated using rather unique advanced cytotoxicity experiments on myeloma and normal blood cells obtained from fresh patient biopsies including newly diagnosed as well as relapsed and treatment-resistant MM. Overall our findings suggest that disulfiram repurposing particularly if combined with copper supplementation may offer a promising and readily available treatment option for patients suffering from relapsed and/or therapy-resistant multiple myeloma.

• MeSH
• Bortezomib pharmacology   therapeutic use   MeSH
• Drug Resistance, Neoplasm MeSH
• Disulfiram pharmacology   MeSH
• Proteasome Inhibitors pharmacology   therapeutic use   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Multiple Myeloma * pathology   MeSH
• Cell Line, Tumor MeSH
• Drug Repositioning MeSH
• Proteasome Endopeptidase Complex metabolism   MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Bortezomib MeSH
• Disulfiram MeSH
• Proteasome Inhibitors MeSH
• Proteasome Endopeptidase Complex MeSH
• Antineoplastic Agents * MeSH