A drug repurposing strategy for overcoming human multiple myeloma resistance to standard-of-care treatment

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F22%3A73612559" target="_blank" >RIV/61989592:15110/22:73612559 - isvavai.cz</a>

Alternative codes found

RIV/00098892:_____/22:10157736

Result on the web

<a href="https://www.nature.com/articles/s41419-022-04651-w" target="_blank" >https://www.nature.com/articles/s41419-022-04651-w</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41419-022-04651-w" target="_blank" >10.1038/s41419-022-04651-w</a>

Result language

angličtina

Original language name

A drug repurposing strategy for overcoming human multiple myeloma resistance to standard-of-care treatment

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10601 - Cell biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cell Death &amp; Disease

ISSN

2041-4889

e-ISSN

—

Volume of the periodical

13

Issue of the periodical within the volume

3

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

203

UT code for WoS article

000764815500006

EID of the result in the Scopus database

2-s2.0-85125808473