ArticleLeukemia2005
Arsenic trioxide (ATO) and MEK1 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells.
Article in Leukemia, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 18 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 52 citations in OpenAlex.
- Synergistic effect of arsenic trioxide and flt3 inhibition on cells with flt3 internal tandem duplication.International journal of hematology · 2006Trial
- MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia.Leukemia · 2023Article
- Mechanistic update of Trisenox in blood cancer.Current research in pharmacology and drug discovery · 2023Review
- Disease-associated metabolic pathways affected by heavy metals and metalloid.Toxicology reports · 2023Review
- Metabolic adaptation drives arsenic trioxide resistance in acute promyelocytic leukemia.Blood advances · 2022Article
- Simulating ATO Mechanism and EGFR Signaling with Fuzzy Logic and Petri Net.Journal of biomedical physics & engineering · 2021Article
- Article
- Arsenic in leukemia: a RSKy business.Cancer biology & therapy · 2013Article
- Article
- Article
- Review
- Targeting PML-RARα and Oncogenic Signaling Pathways by Chinese Herbal Mixture Tien-Hsien Liquid in Acute Promyelocytic Leukemia NB4 Cells.Evidence-based complementary and alternative medicine : eCAM · 2011Article
- Enhancement of arsenic trioxide cytotoxicity by dietary isothiocyanates in human leukemic cells via a reactive oxygen species-dependent mechanism.Leukemia research · 2010Article
- Review
- Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2007Review
- Pro-proliferative function of the long isoform of PML-RARalpha involved in acute promyelocytic leukemia.Oncogene · 2006Article
- Article
- A case of Bowen's disease and small-cell lung carcinoma: long-term consequences of chronic arsenic exposure in Chinese traditional medicine.Environmental health perspectives · 2005Article
Corrections and comments
- Erratum issuedPelicci, P [corrected to Pelicci PG]
Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase (MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-As(R)), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-As(R) cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-As(R) than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-As(R). These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.