Abstract
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.
Highlights
Liver cancer is the sixth most common cancer and the fourth most frequent cause of cancer-related death worldwide[1]
Differential antiproliferative and proapoptotic properties of Sorafenib, Regorafenib, Lenvatinib, and Cabozantinib administered at a regular used in vitro dose (10 μM) in 3D and 2D cultured-differentiated hepatocellular carcinoma (HCC) with different p53 status
The increased antiproliferative and proapoptotic effectiveness of Sorafenib and Regorafenib versus Lenvatinib and Cabozantinib (10 μM) in spheroids was further assessed in 2D cultured HepG2, Hep3B, and Huh[7] cells (24 h, Fig. 3)
Summary
Liver cancer is the sixth most common cancer and the fourth most frequent cause of cancer-related death worldwide[1]. Different phase III clinical trials showed Lenvatinib was statistically non-inferior to Sorafenib in overall median survival as first-line therapy[4], and Regorafenib was Official journal of the Cell Death Differentiation Association. Rodríguez-Hernández et al Cell Death and Disease (2020)11:339 recommended as second-line therapy in patients nonresponsive but tolerant to Sorafenib[5]. The induction of cell death by Sorafenib has been related to a rise in PUMA and BIM, as well as a reduction in induced myeloid leukemia cell differentiation protein (Mcl-1) and survivin[9]. Regorafenib, Lenvatinib, and Cabozantinib have been shown to promote cell death and antiproliferative properties in vitro and in vivo, using different cancer cells lines[11,12,13]
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