Glutathione levels are associated with methotrexate resistance in acute lymphoblastic leukemia cell lines.

Autor:	Canevarolo RR; Centro de Pesquisa Boldrini, Centro Infantil Boldrini, Campinas, SP, Brazil., Melo CPS; Centro de Pesquisa Boldrini, Centro Infantil Boldrini, Campinas, SP, Brazil., Cury NM; Centro de Pesquisa Boldrini, Centro Infantil Boldrini, Campinas, SP, Brazil., Artico LL; Centro de Pesquisa Boldrini, Centro Infantil Boldrini, Campinas, SP, Brazil., Corrêa JR; Centro de Pesquisa Boldrini, Centro Infantil Boldrini, Campinas, SP, Brazil., Tonhasca Lau Y; Centro de Pesquisa Boldrini, Centro Infantil Boldrini, Campinas, SP, Brazil., Mariano SS; Centro de Pesquisa Boldrini, Centro Infantil Boldrini, Campinas, SP, Brazil., Sudalagunta PR; Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States., Brandalise SR; Centro de Pesquisa Boldrini, Centro Infantil Boldrini, Campinas, SP, Brazil., Zeri ACM; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, SP, Brazil., Yunes JA; Centro de Pesquisa Boldrini, Centro Infantil Boldrini, Campinas, SP, Brazil.; Medical Genetics Department, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Dec 01; Vol. 12, pp. 1032336. Date of Electronic Publication: 2022 Dec 01 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.1032336
Abstrakt:	Introduction: Methotrexate (MTX), a folic acid antagonist and nucleotide synthesis inhibitor, is a cornerstone drug used against acute lymphoblastic leukemia (ALL), but its mechanism of action and resistance continues to be unraveled even after decades of clinical use. Methods: To better understand the mechanisms of this drug, we accessed the intracellular metabolic content of 13 ALL cell lines treated with MTX by 1H-NMR, and correlated metabolome data with cell proliferation and gene expression. Further, we validated these findings by inhibiting the cellular antioxidant system of the cells in vitro and in vivo in the presence of MTX. Results: MTX altered the concentration of 31 out of 70 metabolites analyzed, suggesting inhibition of the glycine cleavage system, the pentose phosphate pathway, purine and pyrimidine synthesis, phospholipid metabolism, and bile acid uptake. We found that glutathione (GSH) levels were associated with MTX resistance in both treated and untreated cells, suggesting a new constitutive metabolic-based mechanism of resistance to the drug. Gene expression analyses showed that eight genes involved in GSH metabolism were correlated to GSH concentrations, 2 of which (gamma-glutamyltransferase 1 [GGT1] and thioredoxin reductase 3 [TXNRD3]) were also correlated to MTX resistance. Gene set enrichment analysis (GSEA) confirmed the association between GSH metabolism and MTX resistance. Pharmacological inhibition or stimulation of the main antioxidant systems of the cell, GSH and thioredoxin, confirmed their importance in MTX resistance. Arsenic trioxide (ATO), a thioredoxin inhibitor used against acute promyelocytic leukemia, potentiated MTX cytotoxicity in vitro in some of the ALL cell lines tested. Likewise, the ATO+MTX combination decreased tumor burden and extended the survival of NOD scid gamma (NSG) mice transplanted with patient-derived ALL xenograft, but only in one of four ALLs tested. Conclusion: Altogether, our results show that the cellular antioxidant defense systems contribute to leukemia resistance to MTX, and targeting these pathways, especially the thioredoxin antioxidant system, may be a promising strategy for resensitizing ALL to MTX. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Renatino Canevarolo, Pereira de Souza Melo, Moreno Cury, Luiz Artico, Ronchi Corrêa, Tonhasca Lau, Sousa Mariano, Reddy Sudalagunta, Regina Brandalise, Carolina de Mattos Zeri and Andrés Yunes.)
Databáze:	MEDLINE
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