Apoptosis Response in Acute Lymphoblastic Leukemia Cells after Methotrexate Treatment-A Systematic Review
Article Sidebar
Main Article Content
Abstract
Background: Acute lymphoblastic leukemia (ALL) is a malignancy characterized by the overproduction of immature white blood cells in the bone marrow. Methotrexate (MTX) is a cornerstone chemotherapy agent utilized in ALL treatment due to its ability to induce apoptosis in cancerous cells. MTX’s action involves inhibiting dihydrofolate reductase (DHFR), leading to impaired DNA and RNA synthesis, yet resistance to MTX and its exact apoptotic mechanisms remain areas of ongoing research.
Objective: This systematic review aims to elucidate the mechanisms by which MTX induces apoptosis in ALL cells and to assess the clinical implications of these findings for improving therapeutic strategies.
Methods: Adhering to PRISMA guidelines, databases including Google Scholar, Embase, PubMed, and Web of Science were searched for studies published between 2000 and 2023. Studies were included if they involved MTX treatment of ALL cell lines and assessed apoptosis. Critical Appraisal Skills Programme (CASP) tools were used for quality assessment. Data extraction and thematic analysis were employed to synthesize findings.
Results: Twenty-six studies met the inclusion criteria. Key mechanisms of MTX-induced apoptosis included disruption of mitochondrial membrane potential, activation of the JNK signaling pathway, modulation of BCL-2 family proteins, and interference with folate metabolism. Resistance mechanisms and the therapeutic potential of MTX polyglutamates were also identified.
Conclusion: MTX induces apoptosis in ALL cells through multiple pathways, primarily by disrupting folate metabolism and mitochondrial function. The findings reinforce the necessity for personalized approaches in MTX-based therapy, considering the emerging resistance patterns, and highlight the potential of MTX polyglutamates in enhancing treatment efficacy.
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
References
Morana O, Wood W, Gregory CD. The apoptosis paradox in cancer. International Journal of Molecular Sciences. 2022;23(3):1328.
Ezhilarasan D. Hepatotoxic potentials of methotrexate: Understanding the possible toxicological molecular mechanisms. Toxicology. 2021;458:152840.
Laane E, Panaretakis T, Pokrovskaja K, Buentke E, Corcoran M, Söderhäll S, et al. Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members. Haematologica. 2007;92(11):1460-9.
Shao Y, Tan B, Shi J, Zhou Q. Methotrexate induces astrocyte apoptosis by disrupting folate metabolism in the mouse juvenile central nervous system. Toxicology letters. 2019;301:146-56.
Nanni J, Simonetti G, Marconi G, Fontana MC, Bruno S, Papayannidis C, et al. A three-genes signature of anti-apoptotic genes showed different mechanisms in preventing apoptosis in acute myeloid Leukemia cells and could provide an useful model to establish the proper BH3-mimetich drug or combination. Blood. 2017;130:4969.
Jones , Brophy VH, Krafcik FR, RM K. Methotrexate-induced apoptosis in acute lymphoblastic leukemia cells is mediated by JNK-dependent activation of BIM and enhanced by a BH3 mimetic. BMC cancer. 2015;15(1):61. DOI: 10.1186/s12885-015-1463-8. 2015.
Zhang Q, Liu Y, Li Q, Wu J, Chen R, Y Z. Apoptosis of acute lymphoblastic leukemia cells induced by methotrexate via JNK-dependent FOXO3a nuclear translocation. Cancer letters. 2018 Apr 28;420:1-10. DOI: 10.1016/j.canlet.2018.01.048.. 2018.
Wang Q, Zhou H, Chen X, Shi C, X Z. Methotrexate inhibits the progression of T-cell acute lymphoblastic leukemia by promoting SHP-1-induced apoptosis. Oncology Letters. 2019;17(2):1985-1992. DOI: 10.3892/ol.2019.10518.
Wang S, Cao Y, Chen Z, S Z. Methotrexate induces apoptosis of acute lymphoblastic leukemia cells via JNK-mediated mitochondrial dysfunction. Oncology Reports. 2018;40(2):719-728. doi: 10.3892/or.2018.6497. PMID: 29845298.
Shahbakhsh S, Asnafi AA, Saki N, Hemmati S, Soleimani M, J M-a. Methotrexate-induced DNA damage and chemotherapeutic efficacy in childhood acute lymphoblastic leukemia and lymphoma. Cancer Chemother Pharmacol. 2019 Aug;84(2):269-277. doi: 10.1007/s00280-019-03911-w. Epub 2019 May 21. PMID: 31115614.
Dordal, M. S., Gallego, M. S., Gori, M. S., et al. Methotrexate treatment alters the expression and activity of folate pathway enzymes and transporters in acute lymphoblastic leukemia cells. Leukemia Research, 87, 106238. doi: 10.1016/j.leukres.2019.106238. 2019.
Chen Z, Tang Z. Methotrexate induces apoptosis and enhances chemosensitivity in human acute lymphoblastic leukemia cells through increasing ROS production and downregulating AKT/mTOR pathway. BioMed Research International,. 2019.
Habib S, Saleem M, Ahmad N, Ahmad I, Ahmad M, M A. Methotrexate and chlorambucil induce apoptosis and cell cycle arrest, respectively, in peripheral T-cell lymphoma. Anti-Cancer Drugs. . 2019;30(5).
Vidya Priyadarsini V, Nagini S, D S. Resistance to methotrexate in acute lymphoblastic leukemia cells involves modulation of apoptosis pathway. J Cancer Res Ther. . 2015;11(4):5.
Johnson JM, Castleberry RP, WJ E. Methotrexate Resistance in Acute Lymphoblastic Leukemia: Role of DNA Damage Response Pathways. Front Oncol. . 2019;9.
Erčulj N, Kotnik BF, Debeljak M, Jazbec J, Dolžan V. Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute lymphoblastic leukemia. Leukemia & lymphoma. 2012;53(6):1096-104.
Davidsen ML, Dalhoff K, Schmiegelow K. Pharmacogenetics influence treatment efficacy in childhood acute lymphoblastic leukemia. Journal of pediatric hematology/oncology. 2008;30(11):831-49.
Sorich MJ, Pottier N, Pei D, Yang W, Kager L, Stocco G, et al. In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile. PLoS Medicine. 2008;5(4):e83.
Spurlock III CF, Aune ZT, Tossberg JT, Collins PL, Aune JP, Huston III JW, et al. Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK. Arthritis & Rheumatism. 2011;63(9):2606-16.
Pottier N. PHARMACOGENOMIQUE DES ANTICANCEREUX.
Zhang F, Yu C, Xu W, Li X, Feng J, Shi H, et al. Identification of critical genes and molecular pathways in COVID-19 myocarditis and constructing gene regulatory networks by bioinformatic analysis. Plos one. 2022;17(6):e0269386.
Dong W, Wang B, Zhang R, Cao J, Wu R. Therapeutic effects of acupuncture in rheumatoid arthritis are associated with centromere protein F expression. Allergologia et immunopathologia. 2022;50(3):47-54.
Hsu PP, Do BT, Vermeulen SY, Wang Z, Hirz T, Aziz N, et al. Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress. bioRxiv. 2022:2022.08. 16.503984.
Shafiee A, Shamsi S, Kohandel Gargari O, Beiky M, Allahkarami MM, Miyanaji AB, et al. EBV associated T‐and NK‐cell lymphoproliferative diseases: A comprehensive overview of clinical manifestations and novel therapeutic insights. Reviews in Medical Virology. 2022;32(4):e2328.
Flanagan JM, Funes JM, Henderson S, Wild L, Carey N, Boshoff C. Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets. Molecular cancer therapeutics. 2009;8(1):249-60.
Schmiegelow K, Nielsen SN, Frandsen TL, Nersting J. Mercaptopurine/methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. Journal of pediatric hematology/oncology. 2014;36(7):503.
Adam de Beaumais T, Jacqz-Aigrain E. Intracellular disposition of methotrexate in acute lymphoblastic leukemia in children. Current Drug Metabolism. 2012;13(6):822-34.
Ongaro A, De Mattei M, Della Porta MG, Rigolin G, Ambrosio C, Di Raimondo F, et al. Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival. haematologica. 2009;94(10):1391.
Kodidela S, Suresh Chandra P, Dubashi B. Pharmacogenetics of methotrexate in acute lymphoblastic leukaemia: why still at the bench level? European Journal of Clinical Pharmacology. 2014;70(3):253-60.
Toksvang LN, Lee SH, Yang JJ, Schmiegelow K. Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations. Leukemia. 2022;36(7):1749-58.
Canevarolo RR, Melo CPdS, Cury NM, Artico LL, Corrêa JR, Lau YT, et al. Glutathione levels are associated with methotrexate resistance in acute lymphoblastic leukemia cell lines. Frontiers in Oncology. 2022;12:1032336.
Panieri E, Santoro M. ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell death & disease. 2016;7(6):e2253-e.
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell metabolism. 2016;23(1):27-47.
Zarou MM, Vazquez A, Vignir Helgason G. Folate metabolism: a re-emerging therapeutic target in haematological cancers. Leukemia. 2021;35(6):1539-51.
Wojtuszkiewicz A, Raz S, Stark M, Assaraf YG, Jansen G, Peters GJ, et al. Folylpolyglutamate synthetase splicing alterations in acute lymphoblastic leukemia are provoked by methotrexate and other chemotherapeutics and mediate chemoresistance. International Journal of Cancer. 2016;138(7):1645-56.
Zhang X, Li H, Li X, Zhang W, Zhou M, H C. Methotrexate-induced apoptosis in acute lymphoblastic leukemic cells is mediated by JNK-activated calcium/calmodulin-dependent protein kinase II. Cell Death Dis. 2018;9(5).
Liu J, Xu W, Sun J, Huang Y, X Q. Methotrexate induces apoptosis in acute lymphoblastic leukemia cells via the PTEN/AKT pathway. Oncol Lett. 2019;18:7.
Zhao M, Zhang Y, Hu X, Xu H. Methotrexate induces apoptosis in acute lymphoblastic leukemia cells through upregulation of miR-181a via activation of the JNK signaling pathwayMol Med Rep 2019;19(3): 2133-2142. 2019;19(3):9.
Liu, Zhou M, Luo X, Y L. Methotrexate inhibits the expression of Bcl-2 in acute lymphoblastic leukemia cells and induces apoptosis through the mitochondrial pathway. . Oncol Lett 2018;15(3): 3132-3138. 2018.
Chen , Zhang X, Pan J, H C. Methotrexate induces apoptosis in acute lymphoblastic leukemia cells via JNK-mediated HO-1 overexpression. Oncol Lett. 2019;18(3): 2422-2428. 2019.
Gao J, Wang C, Wei W. The effects of drug transporters on the efficacy of methotrexate in the treatment of rheumatoid arthritis. Life Sciences. 2021;268:118907.