Blockade of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase and Murine Double Minute Synergistically Induces Apoptosis in Acute Myeloid Leukemia via BH3-Only Proteins Puma and Bim
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Abstract
Molecular aberrations of the Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK and/or Murine double minute (MDM2)/p53 signaling pathways have been reported in 80% and 50% of primary acute myeloid leukemia (AML) samples and confer poor outcome. In this study, antileukemic effects of combined MEK inhibition by AZD6244 and nongenotoxic p53 activation by MDM2 antagonist Nutlin-3a were investigated. Simultaneous blockade of MEK and MDM2 signaling by AZD6244 and Nutlin-3a triggered synergistic proapoptotic responses in AML cell lines [combination index (CI) = 0.06 ± 0.03 and 0.43 ± 0.03 in OCI/AML3 and MOLM13 cells, respectively] and in primary AML cells (CI = 0.52 ± 0.01). Mechanistically, the combination upregulated levels of BH3-only proteins Puma and Bim, in part via transcriptional upregulation of the FOXO3a transcription factor. Suppression of Puma and Bim by short interfering RNA rescued OCI/AML3 cells from AZD/Nutlin-induced apoptosis. These results strongly indicate the therapeutic potential of combined MEK/MDM2 blockade in AML and implicate Puma and Bim as major regulators of AML cell survival. Cancer Res; 70(6); 2424–34
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Over 80% of acute myeloid leukaemias have constitutively active MAPK.
“More than 80% of acute myeloid leukaemias (AMLs) express constitutively activated MAPK”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [128]
Half of acute myeloid leukaemias overexpress MDM2.
“and 50% overexpress MDM2 (Ref. 128).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [128]
Nutlin 3a acts synergistically with AZD6244 to trigger apoptosis in acute myeloid leukaemia.
“Nutlin 3a synergizes with AZD6244 (also known as selumetinib), an inhibitor of downstream MAPK signalling, to induce apoptosis in AML128”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [128]
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References 53 · Cited by 70
- Authors
- Zhang, W., Konopleva, M., Burks, J. K., Dywer, K. C., Schober, W. D., Yang, J.-Y., McQueen, T. J., Hung, M.-C., & Andreeff, M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Andreeff, Michael
- ORCID
- Venue
- Cancer Research
- Published
- 2010-03-14
- Volume
- 70
- Issue
- 6
- Pages
- 2424-2434
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2840060
- OpenAlex
- W2096695840
- Cited by
- 70
- References
- 53
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 1 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 5 · 2016: 9 · 2015: 1 · 2014: 11 · 2013: 8 · 2012: 3
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA100632, CA 016672, CA-55164, CA100632, P01CA055164, P30CA016672)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- acute myeloid leukemia, MEK inhibition, MDM2 inhibition, p53 activation, selumetinib, Nutlin-3a, PUMA, building information modeling, BH3-only proteins, FOXO3, apoptosis, combination therapy, RAS/MAPK pathway, MDM2-p53 pathway
- MeSH terms
- Forkhead Box Protein O3, Bcl-2-Like Protein 11, Acute Disease, Benzimidazoles, Drug Synergism, Humans, Imidazoles, Leukemia, Myeloid, Membrane Proteins, Phosphorylation, Piperazines, Proto-Oncogene Proteins, Apoptosis, HL-60 Cells, Proto-Oncogene Proteins c-bcl-2, U937 Cells, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-mdm2, Forkhead Transcription Factors, Myeloid Cell Leukemia Sequence 1 Protein
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