Leni, Zaira; Ćwiek, Paulina; Dimitrova, Valeriya; Dulcey, Andrea S; Zamboni, Nicola; Simillion, Cedric; Rossi, Geetha; Leibundgut, Kurt; Arcaro, Alexandre (2017). 2-Deoxy-D-glucose Restore Glucocorticoid Sensitivity in Acute Lymphoblastic Leukemia via Modification of N-Linked Glycosylation in an Oxygen Tension-Independent Manner. Oxidative medicine and cellular longevity, 2017, p. 2487297. Hindawi 10.1155/2017/2487297
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In childhood acute lymphoblastic leukemia, treatment failure is associated with resistance to glucocorticoid agents. Resistance to this class of drugs represents one of the strongest indicators of poor clinical outcome. We show that leukemic cells, which are resistant to the glucocorticoid drug methylprednisolone, display a higher demand of glucose associated with a deregulation of metabolic pathways, in comparison to sensitive cells. Interestingly, a combinatorial treatment of glucocorticoid and the glucose analog 2-deoxy-D-glucose displayed a synergistic effect in methylprednisolone-resistant cells, in an oxygen tension-independent manner. Unlike solid tumors, where 2-deoxy-D-glucose promotes inhibition of glycolysis by hexokinase II exclusively under hypoxic conditions, we were able to show that the antileukemic effects of 2-deoxy-D-glucose are far more complex in leukemia. We demonstrate a hexokinase II-independent cell viability decrease and apoptosis induction of the glucose analog in leukemia. Additionally, due to the structural similarity of 2-deoxy-D-glucose with mannose, we could confirm that the mechanism by which 2-deoxy-D-glucose predominantly acts in leukemia is via modification in N-linked glycosylation, leading to endoplasmic reticulum stress and consequently induction of the unfolded protein response.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine 04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Paediatric Haematology/Oncology |
UniBE Contributor: |
Leibundgut, Kurt |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1942-0994 |
Publisher: |
Hindawi |
Language: |
English |
Submitter: |
Anette van Dorland |
Date Deposited: |
21 Feb 2018 12:57 |
Last Modified: |
05 Dec 2022 15:10 |
Publisher DOI: |
10.1155/2017/2487297 |
PubMed ID: |
28814986 |
BORIS DOI: |
10.7892/boris.111129 |
URI: |
https://boris.unibe.ch/id/eprint/111129 |
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