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Article

Anti‑cancer effects of a novel Pan‑RAF inhibitor in a hepatocellular carcinoma cell line

  • Authors:
    • Wei Wang
    • Bo Xu
    • Qixiang Li
    • Dechun Jiang
    • Suying Yan
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacy, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, P.R. China, Biomarker and Diagnostic Technology, Crown Bioscience Inc., Beijing 102200, P.R. China
  • Pages: 6185-6193
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    Published online on: February 16, 2018
       https://doi.org/10.3892/mmr.2018.8615
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Abstract

The RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK (RAF/MEK/ERK) signaling cascade serves a prominent role in hepatocellular carcinoma (HCC) proliferation. Sorafenib (BAY 43‑9006) is a potent multikinase inhibitor of RAF kinases and a few receptor tyrosine kinases. Additionally, sorafenib causes apoptosis in a number of human tumor cell lines such as leukemia cell lines. Sorafenib is the first targeted drug to prolong the overall survival of patients with advanced HCC. However, sorafenib activity is less favorable in certain cancers, including sarcomas and melanomas, due to patient insensitivity and drug resistance. In the present study, a novel bi‑aryl urea, N‑(3‑trifluoromethylphenyl)‑N'-(2-methyl-4-(6‑cyclopropanecarboxamido-pyrimidin-4-yl) oxyphenyl) urea (CBI‑5725), is shown to be a potential candidate for the treatment of liver cancer. In the present study, the in vitro activities of CBI‑5725 and sorafenib in PLC/PRF/5 HCC cells were examined and the corresponding in vivo antitumor activities in PLC/PRF/5 human tumor xenografts. An alamar blue assay confirmed that CBI‑5725 was more cytotoxic than sorafenib to PLC/PRF/5 cells, suggesting that CBI‑5725 inhibited tumor cell proliferation more potently than sorafenib. CBI‑5725 inhibited the RAF/MEK/ERK signaling pathway to the same extent as sorafenib. In addition, CBI‑5725 elicited cell cycle arrest in the G2/M phase, while sorafenib did not markedly alter the cell cycle. Furthermore, CBI‑5725 induced apoptosis more strongly than sorafenib in a dose‑dependent manner, which may be attributed to greater caspase‑3 and poly(adenosine 5'‑diphosphate‑ribose) polymerase activation by CBI‑5725. In the PLC/PRF/5 xenograft model, 2 mg/kg CBI‑5725 inhibited tumor growth by 73%. At doses ranging from 6 to 18 mg/kg, CBI‑5725 nearly completely prevented tumor growth. These results imply that the antitumor efficacy of CBI‑5725 in HCC models may result from the suppression of the RAF/MEK/ERK signaling pathway, the induction of cell cycle arrest in the G2/M phase, and the initiation of caspase‑3‑dependent apoptosis. These observations suggested that CBI‑5725 may be a potent novel compound for the treatment of HCC.
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Copy and paste a formatted citation
Spandidos Publications style
Wang W, Xu B, Li Q, Jiang D and Yan S: Anti‑cancer effects of a novel Pan‑RAF inhibitor in a hepatocellular carcinoma cell line. Mol Med Rep 17: 6185-6193, 2018.
APA
Wang, W., Xu, B., Li, Q., Jiang, D., & Yan, S. (2018). Anti‑cancer effects of a novel Pan‑RAF inhibitor in a hepatocellular carcinoma cell line. Molecular Medicine Reports, 17, 6185-6193. https://doi.org/10.3892/mmr.2018.8615
MLA
Wang, W., Xu, B., Li, Q., Jiang, D., Yan, S."Anti‑cancer effects of a novel Pan‑RAF inhibitor in a hepatocellular carcinoma cell line". Molecular Medicine Reports 17.4 (2018): 6185-6193.
Chicago
Wang, W., Xu, B., Li, Q., Jiang, D., Yan, S."Anti‑cancer effects of a novel Pan‑RAF inhibitor in a hepatocellular carcinoma cell line". Molecular Medicine Reports 17, no. 4 (2018): 6185-6193. https://doi.org/10.3892/mmr.2018.8615
Copy and paste a formatted citation
x
Spandidos Publications style
Wang W, Xu B, Li Q, Jiang D and Yan S: Anti‑cancer effects of a novel Pan‑RAF inhibitor in a hepatocellular carcinoma cell line. Mol Med Rep 17: 6185-6193, 2018.
APA
Wang, W., Xu, B., Li, Q., Jiang, D., & Yan, S. (2018). Anti‑cancer effects of a novel Pan‑RAF inhibitor in a hepatocellular carcinoma cell line. Molecular Medicine Reports, 17, 6185-6193. https://doi.org/10.3892/mmr.2018.8615
MLA
Wang, W., Xu, B., Li, Q., Jiang, D., Yan, S."Anti‑cancer effects of a novel Pan‑RAF inhibitor in a hepatocellular carcinoma cell line". Molecular Medicine Reports 17.4 (2018): 6185-6193.
Chicago
Wang, W., Xu, B., Li, Q., Jiang, D., Yan, S."Anti‑cancer effects of a novel Pan‑RAF inhibitor in a hepatocellular carcinoma cell line". Molecular Medicine Reports 17, no. 4 (2018): 6185-6193. https://doi.org/10.3892/mmr.2018.8615
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