Apoptosis Response in Acute Lymphoblastic Leukemia Cells after Methotrexate Treatment-A Systematic Review

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.