Cited by 49Acute Myeloid Leukemia ResearchGenomics, phytochemicals, and oxidative stressCancer-related Molecular Pathways

Anti‐leukaemic effects induced by APR‐246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells

Ali, Dina, Mohammad, Dara K., Mujahed, Huthayfa, Jonson‐Videsäter, Kerstin, Nore, Beston, Paul, Christer, Lehmann, Sören·2016·British Journal of Haematology

Abstract

Summary: The small molecule APR‐246 (PRIMA‐1 MET) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off‐target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up‐regulated. APR‐246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up‐regulated by APR‐246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase‐1 (HMOX1, also termed HO‐1), SLC7A11 and RIT1. Up‐regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up‐regulation and nuclear translocation by APR‐246. Down‐regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR‐246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR‐246‐induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR‐246, resulting in synergistic cell killing together with APR‐246. In conclusion, ROS induction is important for antileukaemic activities of APR‐246 and inhibiting the protective response of the Nrf‐2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.

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Crossref · 10.1111/bjh.14036

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  • Previous unbiased investigation of transcriptome changes in response to eprenetapopt treatment in cancer cells detected no changes to p53 target genes but up-regulation of oxidative stress response genes, including SLC7A11.

    “previous unbiased investigation of the changes to the transcriptome in response to eprenetapopt treatment in cancer cells, which detected no changes to p53 target genes but up-regulation of oxidative stress response genes, including SLC7A11 (13, 35)”

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Authors
Ali, D., Mohammad, D. K., Mujahed, H., Jonson‐Videsäter, K., Nore, B., Paul, C., & Lehmann, S.
Affiliations
  • Karolinska University Hospital (SE)
  • Department of Clinical Immunology Karolinska University Hospital Stockholm Sweden
  • Uppsala University (SE)
Corresponding author
Lehmann, Sören
Venue
British Journal of Haematology
Publisher
Wiley
Published
2016-03-15
Volume
174
Issue
1
Pages
117-126
ISSN
  • 0007-1048 (ISSN-L)
  • 1365-2141
OpenAlex
W2300551564
Cited by
49
References
44
Citations by year
2026: 4 · 2025: 3 · 2024: 1 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 9 · 2019: 5 · 2018: 2 · 2017: 8 · 2016: 1
FWCI
5.07
Type
journal article
Language
en
Open access
closed
Locations
  • British Journal of Haematology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Vetenskapsrådet
  • Stockholms Läns Landsting
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
APR-246, acute myeloid leukemia, TP53 mutation, oxidative stress, reactive oxygen species, Nrf2, heme oxygenase-1, glutathione depletion, PI3K inhibitors, mTOR inhibitors, wortmannin, rapamycin, drug synergy, off-target effects, SLC7A11, RIT1
MeSH terms
Phosphoinositide-3 Kinase Inhibitors, Humans, Quinuclidines, Tumor Cells, Cultured, Leukemia, Myeloid, Acute, Gene Expression Regulation, Leukemic, Tumor Suppressor Protein p53, Oxidative Stress, Protein Kinase Inhibitors, NF-E2-Related Factor 2, Heme Oxygenase-1, TOR Serine-Threonine Kinases

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