Glucose enhances the MTX chemotherapy resistance through CXCR4 expression in acute lymphoblastic leukemia

Qiami, Lemarudin; Anani Sarab, Gholamreza; Sajjadi, Seyed Mehdi; Khodabakhshi, Maryam; Bahraini, Fatemeh; Sayadi, Mahtab

doi:10.61882/JBUMS.32.4.285

Volume 32, Issue 4 (Winter 2026) Journal of Translational Medical Research. 2026, 32(4): 285-294 | Back to browse issues page

‎ 10.61882/JBUMS.32.4.285

Research code: 456764

Ethics code: IR.BUMS.REC.1401.230

Mendeley

Zotero

RefWorks

Qiami L, Anani Sarab G, Sajjadi S M, Khodabakhshi M, Bahraini F, Sayadi M. Glucose enhances the MTX chemotherapy resistance through CXCR4 expression in acute lymphoblastic leukemia. Journal of Translational Medical Research. 2026; 32 (4) :285-294
URL: http://journal.bums.ac.ir/article-1-3567-en.html

Glucose enhances the MTX chemotherapy resistance through CXCR4 expression in acute lymphoblastic leukemia

Lemarudin Qiami¹

, Gholamreza Anani Sarab²

, Seyed Mehdi Sajjadi²

, Maryam Khodabakhshi³

, Fatemeh Bahraini⁴

, Mahtab Sayadi ^*⁵

1- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran & Hematology medical laboratory branch , French Medical Institute for Mothers and Children, Kabul, Afghanistan
2- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
3- Department of Surgical Technology, School of Allied Medical Sciences, Birjand University of Medical Sciences, Birjand, Iran
4- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
5- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran , sayadi.mahtab@yahoo.com

Abstract: (74 Views)

Background and Aims: Diabetes increases the risk of hematological malignancies, including acute lymphoblastic leukemia (ALL). Hyperglycemia-induced glycosylation activates signaling pathways and alters gene expression, including CXCR4, which is associated with resistance to cancer therapy. This study was designed to investigate the effect of a hyperglycemic environment on CXCR4 expression and its role in cell viability and methotrexate (MTX) resistance in ALL.
Materials and Methods: In this in vitro study, Nalm-6 cells were cultured in a high-glucose (hyperglycemic) medium for 10 days to develop a hyperglycemia model. The cells were then divided into four groups: control, MTX (300 nM), high glucose, and high glucose + MTX. Cell viability was assessed after 48 hours using the MTT assay. The mRNA expression level of the CXCR4 gene was measured by quantitative real-time PCR (qRT-PCR), and cell cycle phase analysis was performed by flow cytometry.
Results: Cell viability was 45% in the MTX group and 82% in the high glucose + MTX group. CXCR4 expression increased approximately 25-fold in the high glucose group and 16-fold in the high glucose + MTX group compared to the control group, while MTX alone caused only a slight increase. Cell cycle analysis revealed that MTX treatment arrested cells in the G1 phase regardless of glucose levels, whereas high glucose alone caused an S-phase arrest.
Conclusion: The findings indicated that a hyperglycemic environment upregulated CXCR4 expression, enhanced cell viability in the presence of MTX, and may contribute to chemotherapy resistance in ALL. This highlights a potential link between diabetes-associated hyperglycemia, CXCR4 overexpression, and decreased chemosensitivity in leukemia.

Keywords: Acute Lymphoblastic Leukemia, CXCR4, Diabetes, Glucose, Methotrexate

Full-Text [PDF 616 kb] (40 Downloads)

Type of Study: Original Article | Subject: Hematology
Received: 2025/11/26 | Accepted: 2025/12/29 | ePublished ahead of print: 2026/02/20 | ePublished: 2026/02/20

References

1. Cury NM, Mühlethaler T, Laranjeira ABA, Canevarolo RR, Zenatti PP, Lucena-Agell D, et al. Structural basis of colchicine-site targeting acylhydrazones active against multidrug-resistant acute lymphoblastic leukemia. Iscience. 2019 Nov 22;21:95-109. DOI: 10.1016/j.isci.2019.10.003 [DOI:10.1016/j.isci.2019.10.003] [PMID] []

2. Rastgar A, Sayadi M, Anani-Sarab G, Sajjadi SM. Astaxanthin decreases the growth-inhibitory dose of cytarabine and inflammatory response in the acute lymphoblastic leukemia cell line NALM-6. Mol Biol Rep. 2022;49(7):6415-22. DOI: 10.1007/s11033-022-07452-8 [DOI:10.1007/s11033-022-07452-8] [PMID]

3. Bahraini F, Sayadi M, Safarpour H, Zarban A, Mesbahzadeh B, Sajjadi SM. n-3 polyunsaturated fatty acids enhanced efficacy of cytarabine in iron-overloaded NALM-6 cells via apoptotic and oxidative pathways. Toxicol In Vitro. 2024:105976. DOI: 10.1016/j.tiv.2024.105976 [DOI:10.1016/j.tiv.2024.105976] [PMID]

4. Yadav UP, Singh T, Kumar P, Sharma P, Kaur H, Sharma S, et al. Metabolic adaptations in cancer stem cells. Front Oncol. 2020;10:1010. DOI: 10.3389/fonc.2020.01010 [DOI:10.3389/fonc.2020.01010] [PMID] []

5. Dey S, Murmu N, Mondal T, Saha I, Chatterjee S, Manna R, et al. Multifaceted entrancing role of glucose and its analogue, 2-deoxy-D-glucose in cancer cell proliferation, inflammation, and virus infection. Biomed Pharmacother. 2022;156:113801. DOI: 10.1016/j.biopha.2022.113801 [DOI:10.1016/j.biopha.2022.113801] [PMID]

6. Khalid M, Petroianu G, Adem A. Advanced glycation end products and diabetes mellitus: Mechanisms and perspectives. Biomolecules. 2022;12(4):542. DOI: 10.3390/biom12040542 [DOI:10.3390/biom12040542] [PMID] []

7. Fu Z, R Gilbert E, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev. 2013;9(1):25-53. URL: https://pubmed.ncbi.nlm.nih.gov/22974359/ [DOI:10.2174/157339913804143225] [PMID] []

8. Sharma V, Collins LB, Chen T-h, Herr N, Takeda S, Sun W, et al. Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations. Oncotarget. 2016;7(18):25377-90. DOI: 10.18632/oncotarget.8298 [DOI:10.18632/oncotarget.8298] [PMID] []

9. Abudawood M. Diabetes and cancer: a comprehensive review. Journal of Research in Medical Sciences. J Res Med Sci. 2019 Oct 25;24:94. DOI: 10.4103/jrms.JRMS_242_19 [DOI:10.4103/jrms.JRMS_242_19] [PMID] []

10. Talebpour A, Alipour R, Sajjadi SM, Osmani F, Sarab GA. In Vitro Cytotoxicity of Ferula asafoetida Gum Extract on Human Chronic Myelogenous Leukemia K562 Cells. Pharm Chem J. 2022;56(2):245-53. DOI: 10.1007/s11094-022-02627-w [DOI:10.1007/s11094-022-02627-w]

11. Tsai M-C, Huang H-H, Chou Y-Y, Cheng C-N, Chen J-S, Lin S-J. Risk factors for hyperglycemia during chemotherapy for acute lymphoblastic leukemia among Taiwanese children. Pediatr Neonatol. 2015;56(5):339-45. DOI: 10.1016/j.pedneo.2015.01.008 [DOI:10.1016/j.pedneo.2015.01.008] [PMID]

12. Rots M, Pieters R, Kaspers G, Veerman A, Peters G, Jansen G. Classification of ex vivo methotrexate resistance in acute lymphoblastic and myeloid leukaemia. Br J Haematol. 2000;110(4):791-800. DOI: 10.1046/j.1365-2141.2000.02070.x [DOI:10.1046/j.1365-2141.2000.02070.x] [PMID]

13. Shain K, Tao J. The B-cell receptor orchestrates environment-mediated lymphoma survival and drug resistance in B-cell malignancies. Oncogene. 2014;33(32):4107-13. DOI: 10.1038/onc.2013.379 [DOI:10.1038/onc.2013.379] [PMID] []

14. Konoplev S, Jorgensen JL, Thomas DA, Lin E, Burger J, Kantarjian HM, et al. Phosphorylated CXCR4 is associated with poor survival in adults with B‐acute lymphoblastic leukemia. Cancer. 2011;117(20):4689-95. DOI: 10.1002/cncr.26113 [DOI:10.1002/cncr.26113] [PMID]

15. Peled A, Klein S, Beider K, Burger JA, Abraham M. Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine. 2018;109:11-6. DOI: 10.1016/j.cyto.2018.02.020 [DOI:10.1016/j.cyto.2018.02.020] [PMID]

16. Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019;2(2):141-60. DOI: 10.20517/cdr.2019.10 [DOI:10.20517/cdr.2019.10]

17. Lin X, Xiao Z, Chen T, Liang SH, Guo H. Glucose metabolism on tumor plasticity, diagnosis, and treatment. Front Oncol. 2020;10:317. DOI: 10.3389/fonc.2020.00317 [DOI:10.3389/fonc.2020.00317] [PMID] []

18. Kheyrandish S, Rastgar A, Hamidi M, Sajjadi SM, Sarab GA. Evaluation of anti-tumor effect of the exopolysaccharide from new cold-adapted yeast, Rhodotorula mucilaginosa sp. GUMS16 on chronic myeloid leukemia K562 cell line. Int J Biol Macromol. 2022;206:21-8. DOI: 10.1016/j.ijbiomac.2022.02.113 [DOI:10.1016/j.ijbiomac.2022.02.113] [PMID]

19. Bose S, Zhang C, Le A. Glucose metabolism in cancer: The Warburg effect and beyond. Adv Exp Med Biol. 2021;1311:3-15. DOI: 10.1007/978-3-030-65768-0_1 [DOI:10.1007/978-3-030-65768-0_1] [PMID] []

20. García-Jiménez C, García-Martínez JM, Chocarro-Calvo A, De la Vieja A. A new link between diabetes and cancer: enhanced WNT/β-catenin signaling by high glucose. J Mol Endocrinol. 2014;52(1):R51-R66. DOI: 10.1530/JME-13-0152 [DOI:10.1530/JME-13-0152] [PMID]

21. Mo Y, Wang Y, Zhang L, Yang L, Zhou M, Li X, et al. The role of Wnt signaling pathway in tumor metabolic reprogramming. J Cancer. 2019;10(16):3789-97. DOI: 10.7150/jca.31166 [DOI:10.7150/jca.31166] [PMID] []

22. Chouhan S, Singh S, Athavale D, Ramteke P, Pandey V, Joseph J, et al. Glucose induced activation of canonical Wnt signaling pathway in hepatocellular carcinoma is regulated by DKK4. Sci Rep. Scientific reports. 2016 Jun 8;6(1):27558. DOI: 10.1038/srep27558 [DOI:10.1038/srep27558] [PMID] []

23. Kim D-S, Scherer PE. Obesity, diabetes, and increased cancer progression. Diabetes Metab J. 2021;45(6):799-812. DOI: 10.4093/dmj.2021.0077 [DOI:10.4093/dmj.2021.0077] [PMID] []

24. Huang C-Y, Huang C-Y, Pai Y-C, Lin B-R, Lee T-C, Liang P-H, et al. Glucose metabolites exert opposing roles in tumor chemoresistance. Front Oncol. 2019;9:1282. DOI: 10.3389/fonc.2019.01282 [DOI:10.3389/fonc.2019.01282] [PMID] []

25. Yamamoto M, Acevedo-Duncan M, Chalfant CE, Patel NA, Watson JE, Cooper DR. Acute glucose-induced downregulation of PKC-βII accelerates cultured VSMC proliferation. Am J Physiol Cell Physiol. 2000;279(3):C587-C95. DOI: 10.1152/ajpcell.2000.279.3.C587 [DOI:10.1152/ajpcell.2000.279.3.C587] [PMID]

26. Spurlock III CF, Tossberg JT, Fuchs HA, Olsen NJ, Aune TM. Methotrexate increases expression of cell cycle checkpoint genes via JNK activation. Arthritis & Rheum. 2012;64(6):1780-9. DOI: 10.1002/art.34342 [DOI:10.1002/art.34342] [PMID] []

27. Li X, Guo H, Duan H, Yang Y, Meng J, Liu J, et al. Improving chemotherapeutic efficiency in acute myeloid leukemia treatments by chemically synthesized peptide interfering with CXCR4/CXCL12 axis. Sci Rep. 2015 Nov 5;5:16228. DOI: 10.1038/srep16228 [DOI:10.1038/srep16228] [PMID] []

28. Wang S, Wang X, Liu S, Zhang S, Wei X, Song Y, et al. The CXCR4 antagonist, AMD3100, reverses mesenchymal stem cell-mediated drug resistance in relapsed/refractory acute lymphoblastic leukemia. Onco Targets Ther. 2020;13:6583-91. DOI: 10.2147/OTT.S249425 [DOI:10.2147/OTT.S249425] [PMID] []

29. Nengroo MA, Maheshwari S, Singh A, Verma A, Arya RK, Chaturvedi P, et al. CXCR4 intracellular protein promotes drug resistance and tumorigenic potential by inversely regulating the expression of Death Receptor 5. Cell Death Dis. 2021;12(5):464. DOI: 10.1038/s41419-021-03730-8 [DOI:10.1038/s41419-021-03730-8] [PMID] []

30. Sison EAR, Magoon D, Li L, Annesley CE, Rau RE, Small D, et al. Plerixafor as a chemosensitizing agent in pediatric acute lymphoblastic leukemia: efficacy and potential mechanisms of resistance to CXCR4 inhibition. Oncotarget. 2014;5(19):8947. DOI: 10.18632/oncotarget.2407 [DOI:10.18632/oncotarget.2407] [PMID] []