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

  • Authors:
    • Yuhe Lei
    • Hua Gan
    • Yuqing Huang
    • Yueyue Chen
    • Lei Chen
    • Aiyun  Shan
    • Huan Zhao
    • Mansi Wu
    • Xiaojuan Li
    • Qingyu Ma
    • Jing Wang
    • Enxin  Zhang
    • Jiayan Zhang
    • Yuanxiang Li
    • Feifei Xue
    • Lijuan Deng

  • View Affiliations

  • Published online on: July 30, 2020     https://doi.org/10.3892/ol.2020.11932
  • Article Number: 71

  • Copyright: © Lei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatocellular carcinoma (HCC) remains a challenge in the medical field due to its high malignancy and mortality rates particularly for HCC, which has developed multidrug resistance. Therefore, the identification of efficient chemotherapeutic drugs for multidrug resistant HCC has become an urgent issue. Natural products have always been of significance in drug discovery. In the present study, a cell‑based method was used to screen a natural compound library, which consisted of 78 compounds, and the doxorubicin‑resistant cancer cell line, HepG2/ADM, as screening tools. The findings of the present study led to the shortlisting of one of the compounds, digitoxin, which displayed an inhibitory effect on HepG2/ADM cells, with 50% inhibitory concentration values of 132.65±3.83, 52.29±6.26, and 9.13±3.67 nM for 24, 48, and 72 h, respectively. Immunofluorescence, western blotting and cell cycle analyses revealed that digitoxin induced G2/M cell cycle arrest via the serine/threonine‑protein kinase ATR (ATR)‑serine/threonine‑protein kinase Chk2 (CHK2)‑M‑phase inducer phosphatase 3 (CDC25C) signaling pathway in HepG2/ADM cells, which may have resulted from a DNA double‑stranded break. Digitoxin also induced mitochondrial apoptosis, which was characterized by changes in the interaction between Bcl‑2 and Bax, the release of cytochrome c, as well as the activation of the caspase‑3 and ‑9. To the best of our knowledge, the present study is the first report that digitoxin displays an anti‑HCC effect on HepG2/ADM cells through G2/M cell cycle arrest, which was mediated by the ATR‑CHK2‑CDC25C signaling pathway and mitochondrial apoptosis. Therefore, digitoxin could be a promising chemotherapeutic agent for the treatment of patients with HCC.
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October-2020
Volume 20 Issue 4

Print ISSN: 1792-1074
Online ISSN:1792-1082

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Spandidos Publications style
Lei Y, Gan H, Huang Y, Chen Y, Chen L, Shan A, Zhao H, Wu M, Li X, Ma Q, Ma Q, et al: Digitoxin inhibits proliferation of multidrug‑resistant HepG2 cells through G2/M cell cycle arrest and apoptosis. Oncol Lett 20: 71, 2020.
APA
Lei, Y., Gan, H., Huang, Y., Chen, Y., Chen, L., Shan, A. ... Deng, L. (2020). Digitoxin inhibits proliferation of multidrug‑resistant HepG2 cells through G2/M cell cycle arrest and apoptosis. Oncology Letters, 20, 71. https://doi.org/10.3892/ol.2020.11932
MLA
Lei, Y., Gan, H., Huang, Y., Chen, Y., Chen, L., Shan, A., Zhao, H., Wu, M., Li, X., Ma, Q., Wang, J., Zhang, E., Zhang, J., Li, Y., Xue, F., Deng, L."Digitoxin inhibits proliferation of multidrug‑resistant HepG2 cells through G2/M cell cycle arrest and apoptosis". Oncology Letters 20.4 (2020): 71.
Chicago
Lei, Y., Gan, H., Huang, Y., Chen, Y., Chen, L., Shan, A., Zhao, H., Wu, M., Li, X., Ma, Q., Wang, J., Zhang, E., Zhang, J., Li, Y., Xue, F., Deng, L."Digitoxin inhibits proliferation of multidrug‑resistant HepG2 cells through G2/M cell cycle arrest and apoptosis". Oncology Letters 20, no. 4 (2020): 71. https://doi.org/10.3892/ol.2020.11932