Sorafenib and TRAIL have synergistic effect on hepatocellular carcinoma

Nojiri,Keiichiro; Sugimoto,Kazushi; Shiraki,Katsuya; Tameda,Masahiko; Inagaki,Yuuji; Ogura,Suguru; Kasai,Chika; Kusagawa,Satoko; Yoneda,Misao; Yamamoto,Norihiko; Takei,Yoshiyuki; Nobori,Tsutomu; Ito,Masaaki

doi:10.3892/ijo.2012.1676

Sorafenib and TRAIL have synergistic effect on hepatocellular carcinoma

Authors:
- Keiichiro Nojiri
- Kazushi Sugimoto
- Katsuya Shiraki
- Masahiko Tameda
- Yuuji Inagaki
- Suguru Ogura
- Chika Kasai
- Satoko Kusagawa
- Misao Yoneda
- Norihiko Yamamoto
- Yoshiyuki Takei
- Tsutomu Nobori
- Masaaki Ito
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Affiliations: First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan, Department of Gastroenterology, Mie University School of Medicine, Tsu, Japan, Department of Molecular and Laboratory Medicine, Mie University School of Medicine, Tsu, Japan
Published online on: October 24, 2012 https://doi.org/10.3892/ijo.2012.1676
Pages: 101-108

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Abstract

A multi-kinase inhibitor, sorafenib, was recently approved and is currently recommended for the treatment of advanced hepatocellular carcinoma (HCC). However, HCC treatment outcomes are still poor and necessitate improvement. Therefore, we investigated the influence of sorafenib in combination with each of cytotoxic chemotherapy agents, hypoxia or tumor necrosis factor (TNF)-related apoptosis‑inducing ligand (TRAIL), on cytotoxicity to determine which is the better adjuvant. Additive cytotoxicity of sorafenib to chemotherapy agents, hypoxia and TRAIL, to HCC cells was assessed using cell viability assay. Intracellular levels of anti-apoptotic proteins were determined using western blot analysis. Activation of Wnt/β-catenin signaling was assessed using a luciferase reporter gene assay. Sorafenib significantly and synergistically enhanced the cytotoxicity of TRAIL to HCC cells and 4',6-diamidino-2-phenylindole (DAPI) staining showed increased apoptosis among cells treated with sorafenib and TRAIL. This augmentation in cytotoxicity was derived from sorafenib-mediated downregulation of anti-apoptotic proteins. However, sorafenib did not enhance the cytotoxicity of chemotherapy agents (cisplatin, 5-FU or doxorubicin) or hypoxic treatment to HCC. Moreover, hypoxic treatment induced Wnt/β-catenin signaling activation. Our data showed that in combination TRAIL and sorafenib had a synergistic cytokilling effect on HCC cells and that this effect derived from sorafenib-mediated downregulation of anti-apoptotic proteins.

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