Digitoxin inhibits proliferation of multidrug‑resistant HepG2 cells through G2/M cell cycle arrest and apoptosis

Lei, Yuhe; Gan, Hua; Huang, Yuqing; Chen, Yueyue; Chen, Lei; Shan, Aiyun; Zhao, Huan; Wu, Man-Si; Li, Xiaojuan; Ma, Qingyu; Wang, Jing; Zhang, Enxin; Zhang, Jiayan; Li, Yuanxiang; Xue, Feifei; Deng, Lijuan

doi:10.3892/ol.2020.11932

Cited by 8 publications

(7 citation statements)

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“…We did not observe positivity for pH3 Ser10 , and negativity indicated G2 arrest. Such a finding is consistent with a recently reported study showing ATR-CHK2-CDC25C-mediated G2/M cell cycle arrest after Dg treatment [ 56 ].…”

Section: Resultssupporting

confidence: 93%

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity

Rimpelová

Zimmermann

Drašar

et al. 2021

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Cardiac glycosides (CGs) represent a group of sundry compounds of natural origin. Most CGs are potent inhibitors of Na+/K+-ATPase, and some are routinely utilized in the treatment of various cardiac conditions. Biological activities of other lesser known CGs have not been fully explored yet. Interestingly, the anticancer potential of some CGs was revealed and thereby, some of these compounds are now being evaluated for drug repositioning. However, high systemic toxicity and low cancer cell selectivity of the clinically used CGs have severely limited their utilization in cancer treatment so far. Therefore, in this study, we have focused on two poorly described CGs: hyrcanoside and deglucohyrcanoside. We elaborated on their isolation, structural identification, and cytotoxicity evaluation in a panel of cancerous and noncancerous cell lines, and on their potential to induce cell cycle arrest in the G2/M phase. The activity of hyrcanoside and deglucohyrcanoside was compared to three other CGs: ouabain, digitoxin, and cymarin. Furthermore, by in silico modeling, interaction of these CGs with Na+/K+-ATPase was also studied. Hopefully, these compounds could serve not only as a research tool for Na+/K+-ATPase inhibition, but also as novel cancer therapeutics.

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Section: Resultssupporting

confidence: 93%

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity

Rimpelová

Zimmermann

Drašar

et al. 2021

Foods

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“…As an example, several recent studies have described ubiquitination of Chk1 by TRAF4 to be required for Chk1 phosphorylation. 37 , 38 …”

Section: Discussionmentioning

confidence: 99%

“…As an example, several recent studies have described ubiquitination of Chk1 by TRAF4 to be required for Chk1 phosphorylation. 37,38 The proliferation and viability of the ovarian cancer cell lines SKOV3 and OVCAR8 were significantly decreased with ATR-siRNA or VE-822 treatment in a dose-dependent manner. In line with the proposed mechanism, downregulation of p-ATR was observed after ATR siRNA transfection and VE-822 treatment and produced a concomitant decrease in the expression of p-Chk1, p-Cdc25c, and p-Cdc2.…”

Section: Discussionmentioning

confidence: 99%

ATR and p-ATR are emerging prognostic biomarkers and DNA damage response targets in ovarian cancer

et al. 2020

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Background: Although ataxia-telangiectasia and Rad3 related (ATR) has an established role in the DNA damage response of various cancers, its clinical and prognostic significance in ovarian cancer remains largely unknown. The aims of this study were to assess the expression, function, and clinical prognostic relationship of ATR and phospho-ATR ser428 (p-ATR) in ovarian cancer. Methods: We confirmed ATR and p-ATR expression by immunohistochemistry (IHC) in a unique ovarian cancer tissue microarray constructed of paired primary, recurrent, and metastatic tumor tissues from 26 individual patients. ATR-specific small interfering RNA (siRNA) and ATR inhibitor VE-822 were applied to determine the effects of ATR inhibition on ovarian cancer cell proliferation, apoptosis, and DNA damage. ATR expression and the associated proteins of the ATR/Chk1 pathway in ovarian cancer cell lines were evaluated by Western blotting. The clonogenicity was also examined using clonogenic assays. A three dimensional (3D) cell culture model was performed to mimic the in vivo ovarian cancer environment to further validate the effects of ATR inhibition on ovarian cancer cells. Results: We show recurrent ovarian cancer tissues express higher levels of ATR and p-ATR than their patient-matched primary tumor counterparts. Additionally, higher expression of p-ATR correlates with decreased survival in ovarian cancer patients. Treatment of ovarian cancer cells with ATR specific siRNA or ATR inhibitor VE-822 led to significant apoptosis and inhibition of cellular proliferation, with reduced phosphorylation of Chk1 (p-Chk1), Cdc25c (p-Cdc25c), Cdc2 (p-Cdc2), and increased expression of cleaved PARP and γH2AX. Inhibition of ATR also suppressed clonogenicity and spheroid growth of ovarian cancer cells. Conclusion: Our results support the ATR and p-ATR pathway as a prognostic biomarker, and targeting the ATR machinery is an emerging therapeutic approach in the treatment of ovarian cancer.

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“…As shown in Figures 4(a) and 4(b) , compared with the control group, the cell population in G 2 /M phase significantly increased from 24.48% to 44.61% following 5 μ M evodiamine treatment, suggesting that evodiamine induces G 2 /M cell cycle arrest in DU145 cells. CDK1 and cyclin B1 are key regulators involved in the G 2 /M transition by forming the CDK1/cyclin B1 complex [ 24 ]. Cdc25C activates the CDK1 complex through CDK1 Tyr15 and CDK1 Thr14 dephosphorylation [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Evodiamine as the Active Compound of Evodiae fructus to Inhibit Proliferation and Migration of Prostate Cancer through PI3K/AKT/NF-κB Signaling Pathway

et al. 2022

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Evodiae fructus (EF) is a traditional Chinese medicine which is widely used for the treatment of obesity, inflammation, cardiovascular disease, and diseases of the central nervous system. Recent studies have demonstrated the anticancer property of EF, but the active compounds of EF against prostate cancer and its underlying mechanism remain unknown. In this study, a network pharmacology-based approach was used to explore the multiple ingredients and targets of EF. Through protein-protein interaction (PPI), Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, the potential targets and corresponding ingredients of EF against prostate cancer cells were obtained. CCK8 and colony formation assays were performed to evaluate the antiproliferative effect of the active compounds on DU145 cells. Cell cycle analysis, Annexin V-FITC/PI staining assay, and Hoechst 33258 staining assay were used to explore the way of evodiamine-induced cell death. The capacities of cell migration after evodiamine treatment were evaluated by wound-healing assay. PharmMapper database was used to predict the potential targets of evodiamine against cancer cell migration. Western blot assay was performed to investigate the signaling pathway through which evodiamine inhibits cell proliferation and migration. The binding of evodiamine to PI3K and AKT was verified by molecular docking. As a consequence, 24 active compounds and 141 corresponding targets were obtained through a network pharmacology-based approach. The results of PPI analysis, GO enrichment, and KEGG pathway enrichment indicated that molecules in the PI3K/AKT/NF-κB signaling pathway were the potential targets of EF against prostate cancer, and evodiamine was the potential active compound. In vitro study demonstrated that evodiamine displays antiproliferative effect on DU145 cells obviously. Evodiamine induces G2/M cell cycle arrest by Cdc25c/CDK1/cyclin B1 signaling. Additionally, evodiamine also promotes mitochondrial apoptosis and inhibits cell migration through PI3K/AKT/NF-κB signaling in DU145 cells. In conclusion, evodiamine is the active compound of EF to inhibit proliferation and migration of prostate cancer through PI3K/AKT/NF-κB signaling pathway, indicating that evodiamine may serve as a potential lead drug for prostate cancer treatment.

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Digitoxin inhibits proliferation of multidrug‑resistant HepG2 cells through G2/M cell cycle arrest and apoptosis

Cited by 8 publications

References 61 publications

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity

ATR and p-ATR are emerging prognostic biomarkers and DNA damage response targets in ovarian cancer

Evodiamine as the Active Compound of Evodiae fructus to Inhibit Proliferation and Migration of Prostate Cancer through PI3K/AKT/NF-κB Signaling Pathway

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