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.
Mol Med Rep. 2018 Apr;17(4):6185-6193. doi: 10.3892/mmr.2018.8615. Epub 2018 Feb 16.
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.
RAF/丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）激酶（MEK）/ERK（RAF/MEK/ERK）信号级联在肝细胞癌（HCC）增殖中起着重要作用。索拉非尼（BAY 43-9006）是 RAF 激酶和一些受体酪氨酸激酶的有效多激酶抑制剂。此外，索拉非尼可诱导多种人类肿瘤细胞系（如白血病细胞系）发生细胞凋亡。索拉非尼是第一种延长晚期 HCC 患者总生存期的靶向药物。然而，由于患者的不敏感性和耐药性，索拉非尼在某些癌症中的活性较差，包括肉瘤和黑色素瘤。在本研究中，一种新型双芳基脲，N-（3-三氟甲基苯基）-N'-(2-甲基-4-(6-环丙基羧酰胺嘧啶-4-基)氧苯基)脲（CBI-5725）被证明是治疗肝癌的潜在候选药物。在本研究中，检测了 CBI-5725 和索拉非尼在 PLC/PRF/5 HCC 细胞中的体外活性，并在 PLC/PRF/5 人肿瘤异种移植模型中检测了相应的体内抗肿瘤活性。阿马尔蓝试验证实，CBI-5725 对 PLC/PRF/5 细胞的细胞毒性强于索拉非尼，提示 CBI-5725 比索拉非尼更能抑制肿瘤细胞增殖。CBI-5725 抑制 RAF/MEK/ERK 信号通路的程度与索拉非尼相同。此外，CBI-5725 使细胞周期阻滞在 G2/M 期，而索拉非尼则未明显改变细胞周期。此外，CBI-5725 以剂量依赖性方式诱导比索拉非尼更强的细胞凋亡，这可能归因于 CBI-5725 对 caspase-3 和多聚（腺苷 5'二磷酸核糖）聚合酶的激活作用更强。在 PLC/PRF/5 异种移植模型中，2mg/kg CBI-5725 抑制肿瘤生长 73%。在 6 至 18mg/kg 的剂量范围内，CBI-5725 几乎完全阻止了肿瘤生长。这些结果表明，CBI-5725 在 HCC 模型中的抗肿瘤疗效可能源于 RAF/MEK/ERK 信号通路的抑制、G2/M 期细胞周期阻滞和 caspase-3 依赖性凋亡的诱导。这些观察结果表明，CBI-5725 可能是治疗 HCC 的一种有效新型化合物。
