Digitoxin synergizes with sorafenib to inhibit hepatocelluar carcinoma cell growth without inhibiting cell migration

Xiao,Yijun; Yan,Wei; Guo,Libin; Meng,Chen; Li,Bin; Neves,Henrique; Chen,Peng‑Chen; Li,Ling; Huang,Yide; Kwok,Hang  Fai; Lin,Yao

doi:10.3892/mmr.2016.6096

Digitoxin synergizes with sorafenib to inhibit hepatocelluar carcinoma cell growth without inhibiting cell migration

Authors:
- Yijun Xiao
- Wei Yan
- Libin Guo
- Chen Meng
- Bin Li
- Henrique Neves
- Peng‑Chen Chen
- Ling Li
- Yide Huang
- Hang Fai Kwok
- Yao Lin
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Affiliations: College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, P.R. China, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, P.R. China, The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, P.R. China
Published online on: December 30, 2016 https://doi.org/10.3892/mmr.2016.6096
Pages: 941-947

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Abstract

Sorafenib is a chemotherapeutic agent approved for the treatment of hepatocellular carcinoma (HCC) in China. Digitoxin is a cardiotonic drug, which has been demonstrated to exhibit anticancer effects in a number of cancers, but not in HCC. The aim of the present study was to evaluate the combinational effect of sorafenib and digitoxin on the treatment of HCC and to investigate the relevant molecular mechanisms of action that underlie these effects. The proliferation, cell death and migration of HCC cell lines, HepG2 and BEL‑7402, were examined using MTT, acridine orange/ethidium bromide staining and scratch wound healing assays, respectively. In addition, alterations in the expression of phosphorylated-extracellular signal-regulated kinase (ERK), hypoxia‑inducible factor 1‑α (HIF‑1α), hypoxia‑inducible factor 2‑α (HIF‑2α) and vascular endothelial growth factor (VEGF) were measured prior to and following drug application using western blot analysis. Digitoxin and sorafenib synergistically inhibited cell viability, but did not inhibit migration, which was potentially mediated by suppression of ERK and hypoxia signaling. In downstream signaling pathways, the activity of ERK was synergistically suppressed by combinatorial treatment of HepG2 and BEL‑7402 cells with sorafenib and digitoxin. In addition, the expression of HIF‑1α, HIF‑2α and VEGF was synergistically downregulated by combinational treatment.

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