Picropodophyllin and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells

Tomizawa,Minoru; Shinozaki,Fuminobu; Motoyoshi,Yasufumi; Sugiyama,Takao; Yamamoto,Shigenori; Sueishi,Makoto

doi:10.3892/ol.2014.2484

Picropodophyllin and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells

Authors:
- Minoru Tomizawa
- Fuminobu Shinozaki
- Yasufumi Motoyoshi
- Takao Sugiyama
- Shigenori Yamamoto
- Makoto Sueishi
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Affiliations: Department of Gastroenterology, National Hospital Organization, Shimoshizu Hospital, Yotsukaido, Chiba 284-0003, Japan, Department of Radiology, National Hospital Organization, Shimoshizu Hospital, Yotsukaido, Chiba 284-0003, Japan, Department of Neurology, National Hospital Organization, Shimoshizu Hospital, Yotsukaido, Chiba 284-0003, Japan, Department of Rheumatology, National Hospital Organization, Shimoshizu Hospital, Yotsukaido, Chiba 284-0003, Japan, Department of Pediatrics, National Hospital Organization, Shimoshizu Hospital, Yotsukaido, Chiba 284-0003, Japan
Published online on: August 27, 2014 https://doi.org/10.3892/ol.2014.2484
Pages: 2023-2026

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Abstract

Resistance is one limitation of sorafenib in the treatment of hepatocellular carcinoma (HCC). Insulin-like growth factor-1 receptor (IGF-1R) is involved in cancer cell proliferation. To assess the potential synergistic antitumor effects of picropodophyllin (PPP), an IGF-1R inhibitor, HLF and PLC/PRL/5, HCC cells were treated with PPP alone or PPP in combination with sorafenib, a multikinase inhibitor. Normal human umbilical vein endothelial cells (HUVECs) were also used to analyze the antiangiogenic effects of the drugs. HCC cells and HUVECs were cultured on 96‑well plates, and then treated with PPP, with and without the addition of sorafenib. A 3‑(4,5‑dimethylthiazol‑2‑yl)‑5‑(3‑carboxymethoxyphenyl)‑2‑(4‑sulfophenyl)‑2H‑tetrazolium inner salt assay and hematoxylin and eosin staining were then performed 48 h later. The HCC cells were also analyzed using scratch assays and hematoxylin and eosin staining after 48 h. The proliferation of HLF, PLC/PRF/5 and HUVEC cells was suppressed by the combination of 0.2 µM PPP and 3 µM sorafenib more effectively than by 10 µM sorafenib alone. The motility of HLF and PLC/PRF/5 cells was also suppressed to a greater extent with the combination of PPP at 0.2 µM and sorafenib at 3 µM than with sorafenib at 10 µM alone. The cells that had been treated with 0.2 µM PPP and 3 µM sorafenib also exhibited pyknotic nuclei, which is characteristic of apoptosis. In conclusion, PPP enhanced sorafenib‑mediated suppression of proliferation and motility in HCC cells. Therefore, the combination of PPP and sorafenib may exert antitumor and antiangiogenic effects.

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