Tyrosine kinase inhibitor PTK/ZK enhances the antitumor effects of interferon-α/5-fluorouracil therapy for hepatocellular carcinoma cells

Masahiro Murakami, Shogo Kobayashi, Shigeru Marubashi, Yoshito Tomimaru, Takehiro Noda, Hiroshi Wada, Hidetoshi Eguchi, Yutaka Takeda, Masahiro Tanemura, Koji Umeshita, Yuichiro Doki, Masaki Mori, Hiroaki Nagano

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Purpose: There is no standardized treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus. We previously reported the efficacy of interferon-alpha and 5-fluorouracil combination (IFN/5-FU) therapy for these patients and the potential mechanism via the regulation of vascular endothelial growth factor (VEGF). In this study, we showed the VEGF-related effects of IFN/5-FU therapy using VEGF-receptor (VEGFR) selective inhibitor, PTK787/ZK222584 (PTK/ZK), in HCC cells. Methods: Using two VEGF secreting and VEGFR expressing human HCC cell lines, PLC/PRF/5 and HuH7, we performed growth inhibitory assays in vitro and in vivo, apoptosis assay, cell cycle analysis, and Western blot analysis for the mechanism, with or without PTK/ZK in IFN/5-FU therapy. Results: The combination of PTK/ZK and IFN/5-FU significantly inhibited cell growth in vitro and tended to reduce tumor growth in vivo in a HuH7 xenograft model in nude mice-in both cases without affecting VEGF secretion. PTK/ZK enhanced the IFN/5-FU induced apoptosis, based on increased proteins levels of Bax and reduced Bcl-xL and Bcl-2. Cell cycle analysis showed different results between the HCC cell lines following the combination therapy, possibly due to differences in p21 protein. Conclusions: VEGF signaling inhibition would support an antitumor effect of IFN/5-FU therapy against HCC cell lines via induction of apoptosis and cell cycle delay.

Original languageEnglish
Pages (from-to)589-596
Number of pages8
JournalAnnals of Surgical Oncology
Volume18
Issue number2
DOIs
Publication statusPublished - Feb 1 2011

Fingerprint

Fluorouracil
Protein-Tyrosine Kinases
Interferons
Hepatocellular Carcinoma
Interferon-alpha
Vascular Endothelial Growth Factor A
Cell Cycle
Vascular Endothelial Growth Factor Receptor
Therapeutics
Apoptosis
Cell Line
Growth
bcl-2-Associated X Protein
vatalanib
Portal Vein
Heterografts
Nude Mice
Neoplasms
Thrombosis
Western Blotting

All Science Journal Classification (ASJC) codes

  • Surgery
  • Oncology

Cite this

Tyrosine kinase inhibitor PTK/ZK enhances the antitumor effects of interferon-α/5-fluorouracil therapy for hepatocellular carcinoma cells. / Murakami, Masahiro; Kobayashi, Shogo; Marubashi, Shigeru; Tomimaru, Yoshito; Noda, Takehiro; Wada, Hiroshi; Eguchi, Hidetoshi; Takeda, Yutaka; Tanemura, Masahiro; Umeshita, Koji; Doki, Yuichiro; Mori, Masaki; Nagano, Hiroaki.

In: Annals of Surgical Oncology, Vol. 18, No. 2, 01.02.2011, p. 589-596.

Research output: Contribution to journalArticle

Murakami, M, Kobayashi, S, Marubashi, S, Tomimaru, Y, Noda, T, Wada, H, Eguchi, H, Takeda, Y, Tanemura, M, Umeshita, K, Doki, Y, Mori, M & Nagano, H 2011, 'Tyrosine kinase inhibitor PTK/ZK enhances the antitumor effects of interferon-α/5-fluorouracil therapy for hepatocellular carcinoma cells', Annals of Surgical Oncology, vol. 18, no. 2, pp. 589-596. https://doi.org/10.1245/s10434-010-1310-y
Murakami, Masahiro ; Kobayashi, Shogo ; Marubashi, Shigeru ; Tomimaru, Yoshito ; Noda, Takehiro ; Wada, Hiroshi ; Eguchi, Hidetoshi ; Takeda, Yutaka ; Tanemura, Masahiro ; Umeshita, Koji ; Doki, Yuichiro ; Mori, Masaki ; Nagano, Hiroaki. / Tyrosine kinase inhibitor PTK/ZK enhances the antitumor effects of interferon-α/5-fluorouracil therapy for hepatocellular carcinoma cells. In: Annals of Surgical Oncology. 2011 ; Vol. 18, No. 2. pp. 589-596.
@article{dfb9707e4cd146cd9f836892df457b43,
title = "Tyrosine kinase inhibitor PTK/ZK enhances the antitumor effects of interferon-α/5-fluorouracil therapy for hepatocellular carcinoma cells",
abstract = "Purpose: There is no standardized treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus. We previously reported the efficacy of interferon-alpha and 5-fluorouracil combination (IFN/5-FU) therapy for these patients and the potential mechanism via the regulation of vascular endothelial growth factor (VEGF). In this study, we showed the VEGF-related effects of IFN/5-FU therapy using VEGF-receptor (VEGFR) selective inhibitor, PTK787/ZK222584 (PTK/ZK), in HCC cells. Methods: Using two VEGF secreting and VEGFR expressing human HCC cell lines, PLC/PRF/5 and HuH7, we performed growth inhibitory assays in vitro and in vivo, apoptosis assay, cell cycle analysis, and Western blot analysis for the mechanism, with or without PTK/ZK in IFN/5-FU therapy. Results: The combination of PTK/ZK and IFN/5-FU significantly inhibited cell growth in vitro and tended to reduce tumor growth in vivo in a HuH7 xenograft model in nude mice-in both cases without affecting VEGF secretion. PTK/ZK enhanced the IFN/5-FU induced apoptosis, based on increased proteins levels of Bax and reduced Bcl-xL and Bcl-2. Cell cycle analysis showed different results between the HCC cell lines following the combination therapy, possibly due to differences in p21 protein. Conclusions: VEGF signaling inhibition would support an antitumor effect of IFN/5-FU therapy against HCC cell lines via induction of apoptosis and cell cycle delay.",
author = "Masahiro Murakami and Shogo Kobayashi and Shigeru Marubashi and Yoshito Tomimaru and Takehiro Noda and Hiroshi Wada and Hidetoshi Eguchi and Yutaka Takeda and Masahiro Tanemura and Koji Umeshita and Yuichiro Doki and Masaki Mori and Hiroaki Nagano",
year = "2011",
month = "2",
day = "1",
doi = "10.1245/s10434-010-1310-y",
language = "English",
volume = "18",
pages = "589--596",
journal = "Annals of Surgical Oncology",
issn = "1068-9265",
publisher = "Springer New York",
number = "2",

}

TY - JOUR

T1 - Tyrosine kinase inhibitor PTK/ZK enhances the antitumor effects of interferon-α/5-fluorouracil therapy for hepatocellular carcinoma cells

AU - Murakami, Masahiro

AU - Kobayashi, Shogo

AU - Marubashi, Shigeru

AU - Tomimaru, Yoshito

AU - Noda, Takehiro

AU - Wada, Hiroshi

AU - Eguchi, Hidetoshi

AU - Takeda, Yutaka

AU - Tanemura, Masahiro

AU - Umeshita, Koji

AU - Doki, Yuichiro

AU - Mori, Masaki

AU - Nagano, Hiroaki

PY - 2011/2/1

Y1 - 2011/2/1

N2 - Purpose: There is no standardized treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus. We previously reported the efficacy of interferon-alpha and 5-fluorouracil combination (IFN/5-FU) therapy for these patients and the potential mechanism via the regulation of vascular endothelial growth factor (VEGF). In this study, we showed the VEGF-related effects of IFN/5-FU therapy using VEGF-receptor (VEGFR) selective inhibitor, PTK787/ZK222584 (PTK/ZK), in HCC cells. Methods: Using two VEGF secreting and VEGFR expressing human HCC cell lines, PLC/PRF/5 and HuH7, we performed growth inhibitory assays in vitro and in vivo, apoptosis assay, cell cycle analysis, and Western blot analysis for the mechanism, with or without PTK/ZK in IFN/5-FU therapy. Results: The combination of PTK/ZK and IFN/5-FU significantly inhibited cell growth in vitro and tended to reduce tumor growth in vivo in a HuH7 xenograft model in nude mice-in both cases without affecting VEGF secretion. PTK/ZK enhanced the IFN/5-FU induced apoptosis, based on increased proteins levels of Bax and reduced Bcl-xL and Bcl-2. Cell cycle analysis showed different results between the HCC cell lines following the combination therapy, possibly due to differences in p21 protein. Conclusions: VEGF signaling inhibition would support an antitumor effect of IFN/5-FU therapy against HCC cell lines via induction of apoptosis and cell cycle delay.

AB - Purpose: There is no standardized treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus. We previously reported the efficacy of interferon-alpha and 5-fluorouracil combination (IFN/5-FU) therapy for these patients and the potential mechanism via the regulation of vascular endothelial growth factor (VEGF). In this study, we showed the VEGF-related effects of IFN/5-FU therapy using VEGF-receptor (VEGFR) selective inhibitor, PTK787/ZK222584 (PTK/ZK), in HCC cells. Methods: Using two VEGF secreting and VEGFR expressing human HCC cell lines, PLC/PRF/5 and HuH7, we performed growth inhibitory assays in vitro and in vivo, apoptosis assay, cell cycle analysis, and Western blot analysis for the mechanism, with or without PTK/ZK in IFN/5-FU therapy. Results: The combination of PTK/ZK and IFN/5-FU significantly inhibited cell growth in vitro and tended to reduce tumor growth in vivo in a HuH7 xenograft model in nude mice-in both cases without affecting VEGF secretion. PTK/ZK enhanced the IFN/5-FU induced apoptosis, based on increased proteins levels of Bax and reduced Bcl-xL and Bcl-2. Cell cycle analysis showed different results between the HCC cell lines following the combination therapy, possibly due to differences in p21 protein. Conclusions: VEGF signaling inhibition would support an antitumor effect of IFN/5-FU therapy against HCC cell lines via induction of apoptosis and cell cycle delay.

UR - http://www.scopus.com/inward/record.url?scp=79951558136&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79951558136&partnerID=8YFLogxK

U2 - 10.1245/s10434-010-1310-y

DO - 10.1245/s10434-010-1310-y

M3 - Article

C2 - 20811948

AN - SCOPUS:79951558136

VL - 18

SP - 589

EP - 596

JO - Annals of Surgical Oncology

JF - Annals of Surgical Oncology

SN - 1068-9265

IS - 2

ER -