Targeting sphingolipid metabolism in chronic lymphocytic leukemia.
Leukemia, Lymphocytic, Chronic, B-Cell
/ drug therapy
Humans
Sphingolipids
/ metabolism
Cell Survival
/ drug effects
Glucosyltransferases
/ antagonists & inhibitors
Apoptosis
/ drug effects
Cell Proliferation
/ drug effects
Piperidines
/ pharmacology
Adenine
/ analogs & derivatives
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Glucosylceramides
/ metabolism
Pyrazoles
/ pharmacology
Pyrimidines
/ pharmacology
Chronic lymphocytic leukemia
Drug target
Ibrutinib
Lipidomics
Sphingolipids
Journal
Clinical and experimental medicine
ISSN: 1591-9528
Titre abrégé: Clin Exp Med
Pays: Italy
ID NLM: 100973405
Informations de publication
Date de publication:
30 Jul 2024
30 Jul 2024
Historique:
received:
14
05
2024
accepted:
17
07
2024
medline:
30
7
2024
pubmed:
30
7
2024
entrez:
30
7
2024
Statut:
epublish
Résumé
Elevated levels of circulating C16:0 glucosylceramides (GluCer) and increased mRNA expression of UDP-glucose ceramide glycosyltransferase (UGCG), the enzyme responsible for converting ceramides (Cer) to GluCer, represent unfavorable prognostic markers in chronic lymphocytic leukemia (CLL) patients. To evaluate the therapeutic potential of inhibiting GluCer synthesis, we genetically repressed the UGCG pathway using in vitro models of leukemic B cells, in addition to UGCG pharmacological inhibition with approved drugs such as eliglustat and ibiglustat, both individually and in combination with ibrutinib, assessed in cell models and primary CLL patient cells. Cell viability, apoptosis, and proliferation were evaluated in vitro, and survival and apoptosis were examined ex vivo. UGCG inhibition efficacy was confirmed by quantifying intracellular sphingolipid levels through targeted lipidomics using mass spectrometry. Other inhibitors of sphingolipid biosynthesis pathways were similarly assessed. Blocking UGCG significantly decreased cell viability and proliferation, highlighting the oncogenic role of UGCG in CLL. The efficient inhibition of UGCG was confirmed by a significant reduction in GluCer intracellular levels. The combination of UGCG inhibitors with ibrutinib demonstrated synergistic effect. Inhibitors that target alternative pathways within sphingolipid metabolism, like sphingosine kinases inhibitor SKI-II, also demonstrated promising therapeutic effects both alone and when used in combination with ibrutinib, reinforcing the oncogenic impact of sphingolipids in CLL cells. Targeting sphingolipid metabolism, especially the UGCG pathway, represents a promising therapeutic strategy and as a combination therapy for potential treatment of CLL patients, warranting further investigation.
Identifiants
pubmed: 39078421
doi: 10.1007/s10238-024-01440-x
pii: 10.1007/s10238-024-01440-x
doi:
Substances chimiques
Sphingolipids
0
ibrutinib
1X70OSD4VX
Glucosyltransferases
EC 2.4.1.-
ceramide glucosyltransferase
EC 2.4.1.80
Piperidines
0
Adenine
JAC85A2161
Antineoplastic Agents
0
Glucosylceramides
0
Pyrazoles
0
Pyrimidines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
174Subventions
Organisme : Canada Foundation for Innovation
ID : #37996
Organisme : Canada Foundation for Innovation
ID : #34272
Organisme : CIHR
ID : FRN-167269
Pays : Canada
Organisme : Canada Research Chair in Pharmacogenomics
ID : Tier I CRC-2020-000067
Informations de copyright
© 2024. The Author(s).
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