Department of Pathology, Kurume University School of Medicine, Kurume, Japan
Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
Anticancer Res. 2019 Nov;39(11):5973-5982. doi: 10.21873/anticanres.13802.
BACKGROUND/AIM: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo.
Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined.
Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed.
Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells.
背景/目的：仑伐替尼是一种有效的受体酪氨酸激酶抑制剂，靶向血管内皮生长因子受体（VEGFR1-3）、成纤维细胞生长因子受体（FGFR1-4）、KIT 和 RET。在此，我们研究了仑伐替尼在体外和体内对肝癌细胞的增殖抑制作用。
用 0-30 μM 仑伐替尼处理 11 种肝癌细胞系和 2 种肝细胞癌/胆管细胞癌混合细胞系。检测细胞生长、凋亡以及 FGFR1-4、FGF19、成纤维细胞生长因子受体底物（FRS）2α 和 RET 的表达。将两种 HCC 细胞系皮下植入裸鼠，并用 3、10、30mg/kg/天的仑伐替尼或载体连续治疗 14 天。每 3 天测量肿瘤体积。第 15 天处死小鼠，处理肿瘤进行组织学检查。还检查了血管、微血管密度、坏死和凋亡。
仑伐替尼呈剂量和时间依赖性地抑制所有细胞系的生长，但对仑伐替尼的敏感性存在差异。任何细胞系均未观察到凋亡，这些细胞系中均观察到 FGFR1、-2、-3 和 -4、FGF19、FRS2α 和 RET 的表达。这些因子高表达的细胞系对仑伐替尼的反应更高。在小鼠中，仑伐替尼呈剂量依赖性地抑制肿瘤生长。仑伐替尼显著减少血管和微血管密度，显著增加坏死率；但未观察到凋亡。
仑伐替尼在体外和体内均观察到对肝癌细胞的增殖抑制作用。仑伐替尼可能通过抑制血管生成，以及在一些肝癌细胞中通过额外的直接增殖抑制作用来抑制肿瘤形成。
