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PTK787/ZK222584 Combined with Interferon Alpha and 5-Fluorouracil Synergistically Inhibits VEGF Signaling Pathway in Hepatocellular Carcinoma

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus remains poor. We previously reported the beneficial effects of interferon alpha (IFN) and 5-fluorouracil (5-FU) combination therapy for these patients. We showed that the mechanism of therapy was regulation of vascular endothelial growth factor (VEGF). Here, we combined IFN/5-FU therapy with the VEGF receptor–selective inhibitor PTK787/ZK222584 (PTK/ZK) and examined the antitumor effects and the mechanism of action.

Methods

We studied two HCC cell lines, PLC/PRF/5 and HuH7, and a human umbilical vein endothelial cell line, HUVEC. We studied the effects of IFN/5-FU with or without PTK/ZK in growth inhibition assays, immunohistochemistry, Western blot analysis, and immunocytochemistry.

Results

In a HuH7 xenograft model, the combination of PTK/ZK and IFN/5-FU significantly inhibited proliferation, induced apoptosis, decreased microvessel density, reduced the number of tumor cells that expressed VEGF receptor 2 (VEGFR-2), and repressed the phosphorylation of Akt in vivo. In HCC cells and HUVECs in vitro, IFN/5-FU plus PTK/ZK repressed the expression of VEGFR-2 and repressed the phosphorylation of VEGFR, Akt, Erk, and p38MAPK.

Conclusions

VEGF signaling inhibition enhanced the antitumor effects of IFN/5-FU therapy on HCC cells and endothelial cells via Erk, Akt, and p38MAPK pathways.

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Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan

    Yoshiteru Katsura MD, Hiroshi Wada MD, PhD, Masahiro Murakami MD, PhD, Hirofumi Akita MD, PhD, Naoki Hama MD, PhD, Koichi Kawamoto MD, PhD, Shogo Kobayashi MD, PhD, Shigeru Marubashi MD, PhD, Hidetoshi Eguchi MD, PhD, Masahiro Tanemura MD, PhD, Koji Umeshita MD, PhD, Yuichiro Doki MD, PhD, Masaki Mori MD, PhD & Hiroaki Nagano MD, PhD

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  1. Yoshiteru Katsura MD
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  2. Hiroshi Wada MD, PhD
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  3. Masahiro Murakami MD, PhD
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  4. Hirofumi Akita MD, PhD
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  14. Hiroaki Nagano MD, PhD
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Correspondence to Hiroaki Nagano MD, PhD.

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Katsura, Y., Wada, H., Murakami, M. et al. PTK787/ZK222584 Combined with Interferon Alpha and 5-Fluorouracil Synergistically Inhibits VEGF Signaling Pathway in Hepatocellular Carcinoma. Ann Surg Oncol 20 (Suppl 3), 517–526 (2013). https://doi.org/10.1245/s10434-013-2948-z

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  • DOI: https://doi.org/10.1245/s10434-013-2948-z

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