ArticleScientific reports2017
Mechanisms responsible for the synergistic antileukemic interactions between ATR inhibition and cytarabine in acute myeloid leukemia cells.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 58 citations in OpenAlex.
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- Targeting the DNA damage response in hematological malignancies.Frontiers in oncology · 2024Review
- TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently.Blood advances · 2023Article
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- Pharmacological inhibition of Carbonic Anhydrase IX and XII to enhance targeting of acute myeloid leukaemia cells under hypoxic conditions.Journal of cellular and molecular medicine · 2021Article
- Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment.Experimental hematology & oncology · 2021Review
- The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML.Blood cancer journal · 2021Article
- The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia.Haematologica · 2021Article
- Targeting of PI3K/AKT signaling and DNA damage response in acute myeloid leukemia: a novel therapeutic strategy to boost chemotherapy response and overcome resistance.Cancer drug resistance (Alhambra, Calif.) · 2021Review
- Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy.Signal transduction and targeted therapy · 2020Review
- Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System.Molecules (Basel, Switzerland) · 2020Article
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Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Acute myeloid leukemia (AML) continues to be a challenging disease to treat, thus new treatment strategies are needed. In this study, we investigated the antileukemic effects of ATR inhibition alone or combined with cytarabine in AML cells. Treatment with the ATR-selective inhibitor AZ20 caused proliferation inhibition in AML cell lines and primary patient samples. It partially abolished the G2 cell cycle checkpoint and caused DNA replication stress and damage, accompanied by CDK1-independent apoptosis and downregulation of RRM1 and RRM2. AZ20 synergistically enhanced cytarabine-induced proliferation inhibition and apoptosis, abolished cytarabine-induced S and G2/M cell cycle arrest, and cooperated with cytarabine in inducing DNA replication stress and damage in AML cell lines. These key findings were confirmed with another ATR-selective inhibitor AZD6738. Therefore, the cooperative induction of DNA replication stress and damage by ATR inhibition and cytarabine, and the ability of ATR inhibition to abrogate the G2 cell cycle checkpoint both contributed to the synergistic induction of apoptosis and proliferation inhibition in AML cell lines. Synergistic antileukemic interactions between AZ20 and cytarabine were confirmed in primary AML patient samples. Our findings provide insight into the mechanism of action underlying the synergistic antileukemic activity of ATR inhibition in combination with cytarabine in AML.
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