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Targeting the MAPK/ERK and PI3K/AKT Signaling Pathways Affects NRF2, Trx and GSH Antioxidant Systems in Leukemia

Ewa Jasek-Gajda1, Halina Jurkowska2, Małgorzata Jasińska1

  • 1Department of Histology, Faculty of Medicine, Jagiellonian University Medical College, 31034 Kraków, Poland.

Antioxidants (Basel, Switzerland)
|July 26, 2020
PubMed

Insights

The combination of ERK1/2 inhibitor AZD0364 and PI3K inhibitor ZSTK474 shows synergistic effects against acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) cells. This combination induces oxidative stress and apoptosis, offering a potential new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The mitogen-activated protein kinase (MAPK)/extracellular signal kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathways are crucial in leukemia development.
  • Targeting these pathways presents a potential therapeutic strategy for leukemia treatment.

Purpose of the Study:

  • To investigate the combined effects of ERK1/2 inhibitor AZD0364 and PI3K inhibitor ZSTK474 on various leukemia cell lines.
  • To elucidate the underlying mechanisms of the combined drug action.

Main Methods:

  • Leukemia cell lines (REH, MOLT-4, MOLM-14, K562) were treated with AZD0364 and ZSTK474 alone and in combination.
  • Cell viability, apoptosis, reactive oxygen species (ROS) production, and protein levels (ERK1/2, AKT, NF-κB, NRF2, HO-1, Trx, TrxR, survivin) were assessed.

Main Results:

  • Combined AZD0364 and ZSTK474 demonstrated synergistic effects in ALL (REH, MOLT-4) and AML (MOLM-14) cells, but antagonism in CML (K562) cells.
  • The combination significantly reduced ERK1/2 and AKT activation, inhibited cell viability, increased ROS production, and induced apoptosis.
  • Key alterations in cellular antioxidant defense mechanisms and decreased survivin levels were observed, with cell line-dependent variations.

Conclusions:

  • The combination of AZD0364 and ZSTK474 exhibits synergistic anticancer activity in ALL and AML cells.
  • This synergy is linked to the induction of oxidative stress and modulation of cellular antioxidant defense pathways.
  • The findings suggest a promising therapeutic approach for specific leukemia subtypes.
Keywords:
ERKNRF2PI3Kapoptosisglutathioneleukemiareactive oxygen speciesthioredoxin

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