Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/CSIC/University of Seville, Seville, Spain.
Spanish Network for Biomedical Research in Hepatic and Digestive diseases (CIBERehd), Institute of Health Carlos III (ISCIII), Madrid, Spain.
Cell Death Dis. 2020 May 7;11(5):339. doi: 10.1038/s41419-020-2558-1.
Sorafenib and Regorafenib are the recommended first- and second-line therapies in patients with advanced hepatocellular carcinoma (HCC). Lenvatinib and Cabozantinib have shown non-inferior antitumoral activities compared with the corresponding recommended therapies. The clinical trials have established recommended doses for each treatment that lead different blood concentrations in patients for Sorafenib (10 µM), Regorafenib (1 µM), Lenvatinib (0.1 µM), and Cabozantinib (1 µM). However, very low response rates are observed in patients attributed to intrinsic resistances or upregulation of survival signaling. The aim of the study was the comparative dose-response analysis of the drugs (0-100 µM) in well-differentiated (HepG2, Hep3B, and Huh7), moderately (SNU423), and poorly (SNU449) differentiated liver cancer cells in 2D/3D cultures. Cells harbors wild-type p53 (HepG2), non-sense p53 mutation (Hep3B), inframe p53 gene deletion (SNU423), and p53 point mutation (Huh7 and SNU449). The administration of regular used in vitro dose (10 µM) in 3D and 2D cultures, as well as the dose-response analysis in 2D cultures showed Sorafenib and Regorafenib were increasingly effective in reducing cell proliferation, and inducing apoptosis in well-differentiated and expressing wild-type p53 in HCC cells. Lenvatinib and Cabozantinib were particularly effective in moderately to poorly differentiated cells with mutated or lacking p53 that have lower basal oxygen consumption rate (OCR), ATP, and maximal respiration capacity than observed in differentiated HCC cells. Sorafenib and Regorafenib downregulated, and Lenvatinib and Cabozantinib upregulated epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor receptor (c-Met) in HepG2 cells. Conclusions: Sorafenib and Regorafenib were especially active in well-differentiated cells, with wild-type p53 and increased mitochondrial respiration. By contrast, Lenvatinib and Cabozantinib appeared more effective in moderately to poorly differentiated cells with mutated p53 and low mitochondrial respiration. The development of strategies that allow us to deliver increased doses in tumors might potentially enhance the effectiveness of the treatments.
索拉非尼和瑞戈非尼是晚期肝细胞癌（HCC）患者的首选一线治疗药物。仑伐替尼和卡博替尼与相应的推荐治疗相比，显示出非劣效的抗肿瘤活性。临床试验已经为每种治疗方法确定了推荐剂量，这些剂量导致索拉非尼（10μM）、瑞戈非尼（1μM）、仑伐替尼（0.1μM）和卡博替尼（1μM）在患者体内的血液浓度不同。然而，由于内在耐药性或存活信号的上调，患者的反应率非常低。本研究的目的是在二维/三维培养中对分化良好（HepG2、Hep3B 和 Huh7）、中度（SNU423）和低度（SNU449）分化的肝癌细胞进行药物（0-100μM）的比较剂量-反应分析。细胞携带野生型 p53（HepG2）、无义 p53 突变（Hep3B）、框内 p53 基因缺失（SNU423）和 p53 点突变（Huh7 和 SNU449）。在 3D 和 2D 培养中，给予常规体外使用剂量（10μM），并在 2D 培养中进行剂量反应分析，结果表明索拉非尼和瑞戈非尼在减少细胞增殖和诱导 HCC 细胞中分化良好且表达野生型 p53 的细胞凋亡方面越来越有效。仑伐替尼和卡博替尼在具有突变或缺乏 p53 的中低度分化细胞中特别有效，这些细胞的基础耗氧量（OCR）、ATP 和最大呼吸能力低于分化的 HCC 细胞。索拉非尼和瑞戈非尼下调表皮生长因子受体（EGFR）和间充质上皮转化因子受体（c-Met），仑伐替尼和卡博替尼上调表皮生长因子受体（EGFR）和间充质上皮转化因子受体（c-Met）在 HepG2 细胞中。结论：索拉非尼和瑞戈非尼在分化良好的细胞中特别活跃，这些细胞具有野生型 p53 和增加的线粒体呼吸。相比之下，仑伐替尼和卡博替尼在具有突变 p53 和低线粒体呼吸的中低度分化细胞中似乎更有效。开发使我们能够在肿瘤中给予更高剂量的策略可能会提高治疗效果。
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