The Transfer of Sphingomyelinase Contributes to Drug Resistance in Multiple Myeloma

Abstract

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.

The roles of exosomes in cancer drug resistance and its therapeutic application

“…70 Exosomal acid sphingomyelinase (ASM) is found to confer the resistance to melphalan or bortezomib to sensitive multiple myeloma (MM) cells. 71 It is likely that exosomal ASM mediates the intercellular communication between drug-resistant MM cells and drug-sensitive ones by increasing the release of drug resistance-associated exosomes. Importantly, amitriptyline, which is usually applied to alleviate the pain of MM patients, is found to inhibit ASM expression resulting in the re-sensitivity to melphalan or bortezomib.…”

“…Importantly, amitriptyline, which is usually applied to alleviate the pain of MM patients, is found to inhibit ASM expression resulting in the re-sensitivity to melphalan or bortezomib. 71 Given that the studies about lipid metabolism pathways in exosomeinduced drug resistance are rare, it is interesting to perform lipidomic analysis to identify the differential expression of exosomal lipids in the future. Notably, the diagnostic or prognostic values of identified exosomal lipids should be further verified in a large number of clinical studies.…”

Non-Coding RNAs in Multiple Myeloma Bone Disease Pathophysiology

“…EVs play a crucial role in the context of MM pathobiology, and specifically in the crosstalk that malignant PCs establish with other cells of the BMM such as endothelial, stromal, MSCs and immune cells [ 137 , 138 , 139 , 140 , 141 , 142 ]. Such interaction is key both in the progression of the disease and in the onset of pharmacological resistance [ 143 , 144 ]. Moreover, growing experimental evidence indicates that EVs released by MM cells alter bone homeostasis and, therefore, contribute to the onset of MMBD [ 145 , 146 , 147 , 148 , 149 ].…”

Emerging Insights on the Biological Impact of Extracellular Vesicle-Associated ncRNAs in Multiple Myeloma

“…Accumulating evidence shows that EVs could participate in this process [87,88]. It was found that BMSC-derived EVs isolated from both normal donors and MM patients could induce drug resistance in human MM cells; in fact, EVs increased MM cell viability by 25% in the presence of bortezomib and by 9% in the absence of the drug [87].…”

“…It was found that BMSC-derived EVs isolated from both normal donors and MM patients could induce drug resistance in human MM cells; in fact, EVs increased MM cell viability by 25% in the presence of bortezomib and by 9% in the absence of the drug [87]. Furthermore, Faict and colleagues highlighted that MM cell treatment with melphalan or bortezomib induced the release of EVs with a higher amount of acid sphingomyelinase, which could have a role in the MM drug resistance mechanism [88].…”