ATR-CHK1 pathway as a therapeutic target for acute and chronic leukemias

Boudný, Miroslav; Trbušek, Martin

doi:10.1016/j.ctrv.2020.102026

Cited by 23 publications

(25 citation statements)

References 97 publications

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“…The activation of Myc by RUNX3 had already been demonstrated to be the main cause of the oncogenic function of RUNX3 (30,31). Also, Ddb1, Chek1, and Rad51c are essential genes involved in DNA-damage repair of AML cells (32,33) treatment targets for AML (34). We demonstrated that in murine AML cells, RUNX3 mainly bound these classical genes at their promoter sites.…”

Section: Discussionmentioning

confidence: 60%

“…The activation of Myc by RUNX3 had already been demonstrated to be the main cause of the oncogenic function of RUNX3 ( 30 , 31 ). Also, Ddb1 , Chek1 , and Rad51c are essential genes involved in DNA-damage repair of AML cells ( 32 , 33 ). Bcl2 and Mcl1 are critical antiapoptosis genes and successfully used as treatment targets for AML ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

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Runt-Related Transcription Factor 3 Promotes Acute Myeloid Leukemia Progression

Zhang

Liang

et al. 2021

Front. Oncol.

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Acute myeloid leukemia (AML) is an aggressive hematological malignancy with high relapse/refractory rate. Genetic and epigenetic abnormalities are driving factors for leukemogenesis. RUNX1 and RUNX2 from the Runt-related transcription factor (RUNX) family played important roles in AML pathogenesis. However, the relationship between RUNX3 and AML remains unclear. Here, we found that RUNX3 was a super-enhancer-associated gene and highly expressed in AML cells. The Cancer Genome Atlas (TCGA) database showed high expression of RUNX3 correlated with poor prognosis of AML patients. We observed that Runx3 knockdown significantly inhibited leukemia progression by inducing DNA damage to enhance apoptosis in murine AML cells. By chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we discovered that RUNX3 in AML cells mainly bound more genes involved in DNA-damage repair and antiapoptosis pathways compared to that in normal bone marrow cells. Runx3 knockdown obviously inhibited the expression of these genes in AML cells. Overall, we identified RUNX3 as an oncogene overexpressed in AML cells, and Runx3 knockdown suppressed AML progression by inducing DNA damage and apoptosis.

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Section: Discussionmentioning

confidence: 60%

“…The activation of Myc by RUNX3 had already been demonstrated to be the main cause of the oncogenic function of RUNX3 ( 30 , 31 ). Also, Ddb1 , Chek1 , and Rad51c are essential genes involved in DNA-damage repair of AML cells ( 32 , 33 ). Bcl2 and Mcl1 are critical antiapoptosis genes and successfully used as treatment targets for AML ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

Runt-Related Transcription Factor 3 Promotes Acute Myeloid Leukemia Progression

Zhang

Liang

et al. 2021

Front. Oncol.

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“…Mutations in the ATM-Chk2 pathway are common in malignancies, although mutations in the ATR and Chk1 genes are extremely rare [ 55 ]. This suggests that maintaining the activated ATR-Chk1 pathway is essential for cell survival [ 56 ]. Interestingly, our findings reveal that NNKOAc causes DNA damage, and this results in phosphorylation of ATR, but not phosphorylation of ATM in BEAS-2B cells ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro

et al. 2021

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Lung cancer has the highest mortality rate worldwide and is often diagnosed at late stages, requiring genotoxic chemotherapy with significant side effects. Cancer prevention has become a major focus, including the use of dietary and supplemental antioxidants. Thus, we investigated the ability of an antioxidant formulation (AOX1) to reduce DNA damage in human bronchial epithelial cells (BEAS-2B) with and without the combination of apple peel flavonoid fraction (AF4), or its major constituent quercetin (Q), or Q-3-O-d-glucoside (Q3G) in vitro. To model smoke-related genotoxicity, we used cigarette-smoke hydrocarbon 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) as well as methotrexate (MTX) to induce DNA damage in BEAS-2B cells. DNA fragmentation, γ-H2AX immunofluorescence, and comet assays were used as indicators of DNA damage. Pre-exposure to AOX1 alone or in combination with AF4, Q, or Q3G before challenging with NNKOAc and MTX significantly reduced intracellular reactive oxygen species (ROS) levels and DNA damage in BEAS-2B cells. Although NNKOAc-induced DNA damage activated ATM-Rad3-related (ATR) and Chk1 kinase in BEAS-2B cells, pre-exposure of the cells with tested antioxidants prior to carcinogen challenge significantly reduced their activation and levels of γ-H2AX (p ≤ 0.05). Therefore, AOX1 alone or combined with flavonoids holds promise as a chemoprotectant by reducing ROS and DNA damage to attenuate activation of ATR kinase following carcinogen exposure.

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“…Checkpoint kinase 1 (Chk1) and epidermal growth factor receptor (EGFR) are therapeutic targets for treatment of acute and chronic leukemias [ 152 ] and high-grade serous ovarian cancer [ 153 , 154 ]. Thus, it is significant that compounds 23 , 25 , and 27 have been reported as Chk1 and EGFR tyrosine kinase inhibitors [ 67 , 69 ].…”

Section: Miscellaneous Oxime Group-containing Kinase Inhibitorsmentioning

confidence: 99%

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

et al. 2021

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Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed.

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ATR-CHK1 pathway as a therapeutic target for acute and chronic leukemias

Cited by 23 publications

References 97 publications

Runt-Related Transcription Factor 3 Promotes Acute Myeloid Leukemia Progression

Runt-Related Transcription Factor 3 Promotes Acute Myeloid Leukemia Progression

Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

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