Mechanism of the inhibition of leukemia cell growth and induction of apoptosis through the activation of ATR and PTEN by the topoisomerase inhibitor 3EZ, 20Ac-ingenol

Miyata, Shogo; Fukuda, Yasuaki; Tojima, Haruka; Matsuzaki, Keiichi; Kitanaka, Susumu; Sawada, Hiroshi

doi:10.1016/j.leukres.2015.06.006

Cited by 11 publications

(9 citation statements)

References 48 publications

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“…Camptothecin, the first small molecule targeting Top I for the treatment of advanced digestive carcinoma in clinical2331, which stabilizes the DNA cleavable complex to block the transient breaking and rejoining of DNA173233 and has been used as the Top I poison for the treatment of many digestive solid tumors widely34, was served as the positive control. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Chen

Tian

et al. 2016

Sci Rep

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Crude Amaryllidaceae alkaloids (AAs) extracted from Lycoris radiata are reported to exhibit significant anti-cancer activity. However, the specific alkaloids responsible for the pharmacodynamic activity and their targets still remain elusive. In this context, we strived to combine affinity ultrafiltration with topoisomerase I (Top I) as a target enzyme aiming to fish out specific bioactive AAs from Lycoris radiata. 11 AAs from Lycoris radiata were thus screened out, among which hippeastrine (peak 5) with the highest Enrichment factor (EF) against Top I exhibited good dose-dependent inhibition with IC50 at 7.25 ± 0.20 μg/mL comparable to camptothecin (positive control) at 6.72 ± 0.23 μg/mL. The molecular docking simulation further indicated the inhibitory mechanism between Top I and hippeastrine. The in vitro antiproliferation assays finally revealed that hippeastrine strongly inhibited the proliferation of HT-29 and Hep G2 cells in an intuitive dose-dependent manner with the IC50 values at 3.98 ± 0.29 μg/mL and 11.85 ± 0.20 μg/mL, respectively, and also induced significant cellular morphological changes, which further validated our screening method and the potent antineoplastic effects. Collectively, these results suggested that hippeastrine could be a very promising anticancer candidate for the therapy of cancer in the near future.

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Section: Resultsmentioning

confidence: 99%

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Chen

Tian

et al. 2016

Sci Rep

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“…The PI3K-AKT signalling pathway is an anti-apoptotic pathway that regulates the expression of downstream target proteins, such as Bax and Bcl-2, and thus participates in the regulation of cell growth, apoptosis, differentiation, migration, invasion, and angiogenesis [24,25]. The PTEN protein upstream of the PI3K-AKT signalling pathway can dephosphorylate phosphatidylinositol triphosphate to phosphatidylinositol diphosphate, thereby negatively regulating the PI3K-AKT signalling pathway and playing an important role in apoptosis [26,27].…”

Section: Discussionmentioning

confidence: 99%

Analysis of the miRNA Expression Profiles in the Zearalenone-Exposed TM3 Leydig Cell Line

Wang

et al. 2019

IJMS

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Zearalenone (ZEN), an important environmental pollutant, can cause serious harm to human and animal health. The aim of our study was to examine the effect of zearalenone (ZEN) on miRNA expression profiles in the mouse Leydig cell line (TM3 Leydig cell line) by miRNA sequencing. The effect of ZEN on the viability of TM3 Leydig cells was verified by Cell Counting Kit-8 (CCK-8). MiRNA sequencing was performed 24 h after the exposure of TM3 Leydig cells with 50 μmol/L of ZEN. Bioinformatics predicted the miRNA target genes, performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and conducted miRNA-gene-pathway mapping to show the relationship between miRNA, the target gene, and the signalling pathway. The expression levels of miRNA and the miRNA target genes associated with ZEN toxicology were verified by quantitative real-time polymerase chain reaction. The miRNA sequencing revealed a significant change (p < 0.05) in the 197 miRNAs in the ZEN-treated and control groups, among which 86 were up-regulated and 111 were down-regulated. GO analysis of the target genes of these miRNAs indicated various biological functions. KEGG analysis showed that the predicted miRNA target genes were involved in signalling pathways, such as cancer, apoptosis, and oxidation, namely, the Ras signalling pathway, Rap1 signalling pathway, PI3K-AKT signalling pathway, Foxo signalling pathway, and AMPK signalling pathway. These results suggest that ZEN, as an estrogen-like toxin, is regulated by microRNAs. Our results can help to examine the toxicological effects of ZEN-regulated miRNAs on germ cells.

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“…PTEN is a well-known target gene of miR-19b, which mainly regulates cancer cell growth and proliferation [ 37 – 40 ]. Meanwhile, PTEN overexpression has been reported to increase cellular apoptosis [ 41 – 45 ]. Based on that, we proceeded to investigate whether PTEN could be a downstream effector of miR-19b mediating its effect in H 2 O 2 -induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

miR-19b attenuates H2O2-induced apoptosis in rat H9C2 cardiomyocytesviatargeting PTEN

Tang

Bei

et al. 2016

Oncotarget

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Myocardial ischemia-reperfusion (I-R) injury lacks effective treatments. The miR-17-92 cluster plays important roles in regulating proliferation, apoptosis, cell cycle and other pivotal processes. However, their roles in myocardial I-R injury are largely unknown. In this study, we found that miR-19b was the only member of the miR-17-92 cluster that was downregulated in infarct area of heart samples from a murine model of I-R injury. Meanwhile, downregulation of miR-19b was also detected in H2O2-treated H9C2 cells in vitro mimicking oxidative stress occurring during myocardial I-R injury. Using flow cytometry and Western blot analysis, we found that overexpression of miR-19b decreased H2O2-induced apoptosis and improved cell survival, while downregulation of that had inverse effects. Furthermore, PTEN was negatively regulated by miR-19b at the protein level while silencing PTEN could completely block the aggravated impact of miR-19b inhibitor on H2O2-induced apoptosis in H9C2 cardiomyocytes, indicating PTEN as a downstream target of miR-19b controlling H2O2-induced apoptosis. These data indicate that miR-19b overexpression might be a novel therapy for myocardial I-R injury.

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Mechanism of the inhibition of leukemia cell growth and induction of apoptosis through the activation of ATR and PTEN by the topoisomerase inhibitor 3EZ, 20Ac-ingenol

Cited by 11 publications

References 48 publications

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Antiproliferative activities of Amaryllidaceae alkaloids from Lycoris radiata targeting DNA topoisomerase I

Analysis of the miRNA Expression Profiles in the Zearalenone-Exposed TM3 Leydig Cell Line

miR-19b attenuates H2O2-induced apoptosis in rat H9C2 cardiomyocytesviatargeting PTEN

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