Methotrexate resistance and its regulatory mechanisms in pediatric tumors and beyond.

in Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy by Jing Nie, Lantian Huang, Yan Shen, Hongai Pan, Siwan Wang, Huawei Zhao, Peng Gao, Jufei Yang, Xiaojun Huang, Su Zeng, Jing Miao

TLDR

  • The study reviews methotrexate's therapeutic roles and resistance mechanisms, highlighting the need for multifaceted strategies to overcome resistance and improve treatment outcomes in pediatric tumors and diseases.
  • Key Insights

Abstract

Methotrexate (MTX) is a critical antimetabolite drug in treating various pediatric diseases, including acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), brain tumors, osteosarcoma, inflammatory myofibroblastic tumor (IMT), juvenile scleroderma (JS), and juvenile idiopathic arthritis (JIA). MTX acts as a folate antagonist by inhibiting dihydrofolate reductase (DHFR), an enzyme essential for the synthesis of tetrahydrofolate. This disruption impairs DNA synthesis, repair, and cellular replication, particularly affecting rapidly dividing cells. Despite its efficacy, MTX resistance poses significant challenges, particularly in pediatric oncology, where it undermines the ability to achieve sustained therapeutic effects, resulting in reduced therapeutic efficacy and poor prognosis. The mechanisms of MTX resistance encompassed reduced enzyme activity pivotal for MTX metabolism, enhanced expression of efflux transporters, genetic variations, and alterations in signaling pathways. Multifaceted strategies have been explored to overcome MTX resistance. Combination therapies with ginger extract, gold nanoparticles, and arsenic trioxide (ATO) have been investigated to augment MTX's cytotoxic effects. Synergies with mTOR inhibitors and MDM2 inhibitors have demonstrated enhanced outcomes in ALL. In JIA, targeting ATP-binding cassette (ABC) transporters and modulating transforming growth factor‑β (TGF-β) signaling pathways have emerged as promising approaches. For osteosarcoma, emphasis on autophagy pathways and non-coding RNAs influencing chemotherapy sensitivity could enhance MTX effectiveness. This review delineates MTX's therapeutic roles, elucidates its resistance mechanisms, and discusses current and potential strategies for managing MTX resistance to bolster treatment effectiveness in pediatric tumors and other diseases. This knowledge base could underpin further research and development of personalized treatments to optimize MTX's clinical benefits.

Overview

  • The study discusses methotrexate (MTX), a critical antimetabolite drug in treating various pediatric diseases, including acute lymphoblastic leukemia, non-Hodgkin lymphoma, brain tumors, and others.
  • MTX acts as a folate antagonist, disrupting DNA synthesis, repair, and cellular replication by inhibiting dihydrofolate reductase (DHFR).
  • The study aims to review MTX's therapeutic roles, elucidate its resistance mechanisms, and discuss strategies for managing MTX resistance to improve treatment effectiveness in pediatric tumors and diseases.

Comparative Analysis & Findings

  • MTX resistance poses significant challenges, particularly in pediatric oncology, where it undermines the ability to achieve sustained therapeutic effects, resulting in reduced therapeutic efficacy and poor prognosis.
  • The mechanisms of MTX resistance include reduced enzyme activity, enhanced expression of efflux transporters, genetic variations, and alterations in signaling pathways.
  • Combination therapies with ginger extract, gold nanoparticles, and arsenic trioxide (ATO) have been investigated to augment MTX's cytotoxic effects, while synergies with mTOR inhibitors and MDM2 inhibitors have demonstrated enhanced outcomes in ALL.

Implications and Future Directions

  • The study highlights the importance of understanding MTX resistance mechanisms and exploring multidisciplinary strategies to overcome resistance and improve treatment outcomes.
  • Targeting ATP-binding cassette (ABC) transporters and modulating transforming growth factor-β (TGF-β) signaling pathways have emerged as promising approaches in JIA and other diseases.
  • Further research is needed to develop personalized treatments and optimize MTX's clinical benefits in pediatric tumors and diseases, focusing on autophagy pathways, non-coding RNAs, and other mechanisms.
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