Low dose of 2-deoxy-D-glucose kills acute lymphoblastic leukemia cells and reverses glucocorticoid resistance via N-linked glycosylation inhibition under normoxia
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Ling Gu1,*, Zhihui Yi2,*, Yanle Zhang1, Zhigui Ma1, Yiping Zhu1, Ju Gao1
1Laboratory of Hematology/Oncology, Department of Pediatric Hematology/Oncology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
2Department of Gastroenterology, West China University Hospital, Sichuan University, Chengdu, China
*These authors contributed equally to this work and should be considered co-first authors
Ling Gu, email: [email protected]
Keywords: 2-deoxy-D-glucose, glycolysis, glucocorticoid resistance, acute lymphoblastic leukemia, N-Linked glycosylation
Received: November 02, 2016 Accepted: February 28, 2017 Published: March 09, 2017
Recent studies showed that 2-deoxy-D-glucose (2-DG), a glucose analog with dual activity of inhibiting glycolysis and N-linked glycosylation, can be selectively taken up by cancer cells and be used as a potential chemo- and radio-sensitizer. Meanwhile, 2-DG can kill cancer cells under normoxia. However, its efficacy is limited by the high-dose induced systemic toxicity. Here, we showed that low-dose 2-DG could be used as a single agent to kill acute lymphoblastic leukemia (ALL) cells, and as a GC sensitizer to overcome GC resistance under normoxia. Addition of exogenous mannose, a sugar essential for N-linked glycosylation, rescued 2-DG-treated ALL cells, indicating that inhibition of N-linked glycosylation and induction of endoplasmic reticulum stress is the main mechanism for 2-DG to induce cell death and reverse GC resistance in ALL cells. These data provides new insight into the molecular mechanisms involved in GC resistance. More important, it indicates that 2-DG might be the promising drug for designing novel high efficiency and low toxic protocol for ALL patients.
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