Abstract
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.
Highlights
Multiple myeloma (MM), the second most frequent hematologic malignancy represents a still incurable plasma cell disease [1, 2]
Alternative approaches to target proteasome or more generally the ubiquitin-proteasome degradation system (UPS) are under preclinical testing for MM treatment. These approaches include targeting 19 S proteasome components such as deubiquitinases POH1 [5] and USP14/UCHL5 [6] or ubiquitin-binding receptor RPN13 [7]. These inhibitors were effective against MM in vitro and in vivo, induced accumulation of ubiquitinated proteins, and activation of the cellular unfolded protein response (UPR) – a stress pathway leading to cell death [8–10]
Treatment of cells with CuET evokes phenotypes resembling inhibitors of protein degradation such as bortezomib or p97 [12, 31] via inhibition and aggregation of NPL4, an essential cofactor of p97 segregase [31, 46] involved in protein degradation upstream of the proteasome
Summary
Multiple myeloma (MM), the second most frequent hematologic malignancy represents a still incurable plasma cell disease [1, 2]. Both AMO1 and MM1.S cells showed One of the suggested resistance mechanisms of MM cells elevated K48-Ub smears compared to MDA-MB-231 and U2OS cells towards PIs reflects attenuated proteosynthetic activity In such suggesting a relationship to CuET-sensitivity As MM cells grow synthesis are closely interconnected [20] Such a in suspension, we assessed whether CuET induces the same universal resistance mechanism of MM cells might impact phenotypes as published for other cell lines including proteasome- responses to inhibitors targeting the protein degradation inhibition-like response, UPR and heat-shock response (HSR) [31].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
