Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
Department of Surgical Oncology, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
J Cell Mol Med. 2009 Aug;13(8B):2673-2683. doi: 10.1111/j.1582-4934.2009.00692.x. Epub 2009 Feb 9.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Vascular endothelial growth factor, platelet derived growth factor and the Raf/mitogen-activated protein kinase/extracellular signal regulated kinase (Raf/MEK/ERK) signalling pathway regulates the growth, neovascularization, invasiveness and metastatic potential of HCC. In this study, we investigated the in vivo antitumour activity and mechanisms of action of sorafenib tosylate on four patient-derived HCC xenografts. Sorafenib dosed at 50 mg/kg and 100 mg/kg inhibited tumour growth by 85% and 96%, respectively. Sorafenib-induced growth suppression and apoptosis were associated with inhibition of angiogenesis, down-regulation of phospho-platelet-derived growth factor receptor beta Tyr1021, phospho-eIF4E Ser209, phospho-c-Raf Ser259, c-Raf, Mcl-1, Bcl-2, Bcl-x and positive cell cycle regulators, up-regulation of apoptosis signalling kinase-1, p27 and p21. Expression of IGF-1Rbeta and phosphorylation of c-Raf Ser338, MEK1/2 Ser217/221 and ERK1/2 Thr202/Tyr204 were increased by sorafenib treatment. Phosphorylation of mammalian target-of-rapamycin (mTOR) targets (p70S6K, S6R and 4EBP1) was reduced by sorafenib in sorafenib-sensitive lines but activated in sorafenib-less-sensitive 10-0505 xenograft. Sorafenib-induced phosphorylation of c-met, p70S6K and 4EBP1 was significantly reduced when 10-0505 cells were co-treated with anti-human anti-HGF antibody, suggesting that treatment with sorafenib leads to increased HGF secretion and activation of c-met and mTOR targets. Treatment of 10-0505 tumours with sorafenib plus rapamycin resulted in growth inhibition, inhibition of vascular endothelial growth factor receptor-2 phosphorylation, increased apoptosis and completely blocked sorafenib-induced phosphorylation of mTOR targets and cyclin B1 expression. These data also provide a strong rationale for clinical investigation of sorafenib in combination with mTOR inhibitors in patients with HCC.
肝细胞癌（HCC）是全球第五大常见恶性肿瘤。血管内皮生长因子、血小板衍生生长因子和 Raf/丝裂原活化蛋白激酶/细胞外信号调节激酶（Raf/MEK/ERK）信号通路调节 HCC 的生长、新生血管形成、侵袭和转移潜能。在这项研究中，我们研究了索拉非尼甲苯磺酸盐对四个患者来源的 HCC 异种移植物的体内抗肿瘤活性和作用机制。索拉非尼剂量为 50mg/kg 和 100mg/kg 时，肿瘤生长分别抑制 85%和 96%。索拉非尼诱导的生长抑制和细胞凋亡与血管生成抑制、磷酸化血小板衍生生长因子受体β Tyr1021、磷酸化 eIF4E Ser209、磷酸化 c-Raf Ser259、c-Raf、Mcl-1、Bcl-2、Bcl-x 和阳性细胞周期调节剂下调、凋亡信号激酶-1、p27 和 p21 上调有关。IGF-1Rβ 的表达和 c-Raf Ser338、MEK1/2 Ser217/221 和 ERK1/2 Thr202/Tyr204 的磷酸化被索拉非尼治疗所增加。索拉非尼在索拉非尼敏感系中降低了哺乳动物雷帕霉素靶蛋白（mTOR）靶标（p70S6K、S6R 和 4EBP1）的磷酸化，但在索拉非尼不敏感的 10-0505 异种移植物中激活。当 10-0505 细胞与抗人抗 HGF 抗体共同处理时，索拉非尼诱导的 c-met、p70S6K 和 4EBP1 的磷酸化显著降低，这表明索拉非尼治疗导致 HGF 分泌增加，激活 c-met 和 mTOR 靶标。索拉非尼加雷帕霉素治疗 10-0505 肿瘤导致生长抑制、血管内皮生长因子受体-2 磷酸化抑制、凋亡增加，并完全阻断索拉非尼诱导的 mTOR 靶标和细胞周期蛋白 B1 表达的磷酸化。这些数据还为 HCC 患者索拉非尼联合 mTOR 抑制剂的临床研究提供了强有力的依据。
