Metabolic profile of leukemia cells influences treatment efficacy of L-asparaginase.
Adolescent
Antineoplastic Agents
/ pharmacology
Asparaginase
/ pharmacology
Biosynthetic Pathways
/ drug effects
Bone Marrow
/ pathology
Cell Line, Tumor
Child
Child, Preschool
Drug Resistance, Neoplasm
Female
Glycolysis
/ drug effects
Humans
Infant
Male
Membrane Potential, Mitochondrial
/ drug effects
Metabolome
/ drug effects
Mitochondria
/ drug effects
Oxidative Phosphorylation
/ drug effects
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ blood
Treatment Outcome
Young Adult
L-asparaginase
cancer metabolism
fatty acid oxidation
glycolysis
leukemia
mitochondrial membrane potential
mitochondrial respiration
resistance
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
05 Jun 2020
05 Jun 2020
Historique:
received:
27
04
2020
accepted:
28
05
2020
entrez:
7
6
2020
pubmed:
7
6
2020
medline:
20
1
2021
Statut:
epublish
Résumé
Effectiveness of L-asparaginase administration in acute lymphoblastic leukemia treatment is mirrored in the overall outcome of patients. Generally, leukemia patients differ in their sensitivity to L-asparaginase; however, the mechanism underlying their inter-individual differences is still not fully understood. We have previously shown that L-asparaginase rewires the biosynthetic and bioenergetic pathways of leukemia cells to activate both anti-leukemic and pro-survival processes. Herein, we investigated the relationship between the metabolic profile of leukemia cells and their sensitivity to currently used cytostatic drugs. Altogether, 19 leukemia cell lines, primary leukemia cells from 26 patients and 2 healthy controls were used. Glycolytic function and mitochondrial respiration were measured using Seahorse Bioanalyzer. Sensitivity to cytostatics was measured using MTS assay and/or absolute count and flow cytometry. Mitochondrial membrane potential was determined as TMRE fluorescence. Using cell lines and primary patient samples we characterized the basal metabolic state of cells derived from different leukemia subtypes and assessed their sensitivity to cytostatic drugs. We found that leukemia cells cluster into distinct groups according to their metabolic profile. Lymphoid leukemia cell lines and patients sensitive to L-asparaginase clustered into the low glycolytic cluster. While lymphoid leukemia cells with lower sensitivity to L-asparaginase together with resistant normal mononuclear blood cells gathered into the high glycolytic cluster. Furthermore, we observed a correlation of specific metabolic parameters with the sensitivity to L-asparaginase. Greater ATP-linked respiration and lower basal mitochondrial membrane potential in cells significantly correlated with higher sensitivity to L-asparaginase. No such correlation was found in the other cytostatic drugs tested by us. These data support that cell metabolism plays a prominent role in the treatment effect of L-asparaginase. Based on these findings, leukemia patients with lower sensitivity to L-asparaginase with no specific genetic characterization could be identified by their metabolic profile.
Sections du résumé
BACKGROUND
BACKGROUND
Effectiveness of L-asparaginase administration in acute lymphoblastic leukemia treatment is mirrored in the overall outcome of patients. Generally, leukemia patients differ in their sensitivity to L-asparaginase; however, the mechanism underlying their inter-individual differences is still not fully understood. We have previously shown that L-asparaginase rewires the biosynthetic and bioenergetic pathways of leukemia cells to activate both anti-leukemic and pro-survival processes. Herein, we investigated the relationship between the metabolic profile of leukemia cells and their sensitivity to currently used cytostatic drugs.
METHODS
METHODS
Altogether, 19 leukemia cell lines, primary leukemia cells from 26 patients and 2 healthy controls were used. Glycolytic function and mitochondrial respiration were measured using Seahorse Bioanalyzer. Sensitivity to cytostatics was measured using MTS assay and/or absolute count and flow cytometry. Mitochondrial membrane potential was determined as TMRE fluorescence.
RESULTS
RESULTS
Using cell lines and primary patient samples we characterized the basal metabolic state of cells derived from different leukemia subtypes and assessed their sensitivity to cytostatic drugs. We found that leukemia cells cluster into distinct groups according to their metabolic profile. Lymphoid leukemia cell lines and patients sensitive to L-asparaginase clustered into the low glycolytic cluster. While lymphoid leukemia cells with lower sensitivity to L-asparaginase together with resistant normal mononuclear blood cells gathered into the high glycolytic cluster. Furthermore, we observed a correlation of specific metabolic parameters with the sensitivity to L-asparaginase. Greater ATP-linked respiration and lower basal mitochondrial membrane potential in cells significantly correlated with higher sensitivity to L-asparaginase. No such correlation was found in the other cytostatic drugs tested by us.
CONCLUSIONS
CONCLUSIONS
These data support that cell metabolism plays a prominent role in the treatment effect of L-asparaginase. Based on these findings, leukemia patients with lower sensitivity to L-asparaginase with no specific genetic characterization could be identified by their metabolic profile.
Identifiants
pubmed: 32503472
doi: 10.1186/s12885-020-07020-y
pii: 10.1186/s12885-020-07020-y
pmc: PMC7275298
doi:
Substances chimiques
Antineoplastic Agents
0
Asparaginase
EC 3.5.1.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
526Subventions
Organisme : Ministerstvo Zdravotnictví Ceské Republiky
ID : NV18-07-00129
Organisme : Grantová Agentura České Republiky
ID : 16-12726S
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