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Metabolic profile of leukemia cells influences treatment efficacy of L-asparaginase
K. Hlozkova, A. Pecinova, N. Alquezar-Artieda, D. Pajuelo-Reguera, M. Simcikova, L. Hovorkova, K. Rejlova, M. Zaliova, T. Mracek, A. Kolenova, J. Stary, J. Trka, J. Starkova
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články
Grantová podpora
NV18-07-00129
Ministerstvo Zdravotnictví Ceské Republiky
16-12726S
Grantová Agentura České Republiky
NLK
BioMedCentral
od 2001-12-01
BioMedCentral Open Access
od 2001
Directory of Open Access Journals
od 2001
Free Medical Journals
od 2001
PubMed Central
od 2001
Europe PubMed Central
od 2001
ProQuest Central
od 2009-01-01
Open Access Digital Library
od 2001-01-01
Open Access Digital Library
od 2001-01-01
Open Access Digital Library
od 2001-01-01
Medline Complete (EBSCOhost)
od 2001-01-01
Health & Medicine (ProQuest)
od 2009-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2001
Springer Nature OA/Free Journals
od 2001-12-01
- MeSH
- akutní lymfatická leukemie krev farmakoterapie patologie MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- asparaginasa farmakologie terapeutické užití MeSH
- biosyntetické dráhy účinky léků MeSH
- chemorezistence MeSH
- dítě MeSH
- glykolýza účinky léků MeSH
- kojenec MeSH
- kostní dřeň patologie MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- metabolom účinky léků MeSH
- mitochondrie účinky léků metabolismus MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádorové buněčné linie MeSH
- oxidativní fosforylace účinky léků MeSH
- předškolní dítě MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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: 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: 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: 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.
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- $a Hlozkova, Katerina $u CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic $u Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
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- $a 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: 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: 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: 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.
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