The Transfer of Sphingomyelinase Contributes to Drug Resistance in Multiple Myeloma

Sylvia Faict, Inge Oudaert, Ludovic D'Auria, Jonas Dehairs, Ken Maes, Philip Vlummens, Kim De Veirman, Elke De Bruyne, Karel Fostier, Isabelle Vande Broek, Rik Schots, Karin Vanderkerken, Johannes V Swinnen, Eline Menu

Onderzoeksoutput: Articlepeer review

34 Citaten (Scopus)
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Samenvatting

Multiple myeloma (MM) is well-known for the development of drug resistance, leading to relapse. Therefore, finding novel treatment strategies remains necessary. By performing a lipidomics assay on MM patient plasma, we aimed to identify new targets. We observed a dysregulation in the sphingolipid metabolism, with the upregulation of several ceramides and downregulation of sphingomyelin. This imbalance suggests an increase in sphingomyelinase, the enzyme responsible for hydrolyzing sphingomyelin into ceramide. We confirmed the upregulation of acid sphingomyelinase (ASM) in primary MM cells. Furthermore, we observed an increase in ASM expression in MM cell lines treated with melphalan or bortezomib, as well as in their exosomes. Exosomes high in ASM content were able to transfer the drug-resistant phenotype to chemosensitive cells, hereby suggesting a tumor-protective role for ASM. Finally, inhibition of ASM by amitriptyline improved drug sensitivity in MM cell lines and primary MM cells. In summary, this study is the first to analyze differences in plasma lipid composition of MM patients and match the observed differences to an upregulation of ASM. Moreover, we demonstrate that amitriptyline is able to inhibit ASM and increase sensitivity to anti-myeloma drugs. This study, therefore, provides a rational to include ASM-targeting-drugs in combination strategies in myeloma patients.

Originele taal-2English
Artikelnummer1823
TijdschriftCancers
Volume11
Nummer van het tijdschrift12
DOI's
StatusPublished - 20 nov 2019

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