RT Journal Article
T1 Differential effectiveness of tyrosine kinase inhibitors in 2D/3D culture according to cell differentiation, p53 status and mitochondrial respiration in liver cancer cells.
A1 Rodriguez-Hernandez, Maria A
A1 Chapresto-Garzon, Raquel
A1 Cadenas, Miryam
A1 Navarro-Villaran, Elena
A1 Negrete, Maria
A1 Gomez-Bravo, Miguel A
A1 Victor, Victor M
A1 Padillo, Francisco J
A1 Muntane, Jordi
K1 Predictive markers
K1 Liver cancer
AB 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.
PB Nature Publishing Group
YR 2020
FD 2020-05-07
LK http://hdl.handle.net/10668/15529
UL http://hdl.handle.net/10668/15529
LA en
NO Rodríguez-Hernández MA, Chapresto-Garzón R, Cadenas M, Navarro-Villarán E, Negrete M, et al. Differential effectiveness of tyrosine kinase inhibitors in 2D/3D culture according to cell differentiation, p53 status and mitochondrial respiration in liver cancer cells. Cell Death Dis. 2020 May 7;11(5):339.
NO We thank Dr. Bernhard Brüne (Institute of Biochemistry , Faculty of Medicine , Goethe- University Frankfurt, Frankfurt, Germany ) for his technical assistance in developing 3D culture of liver cancer cells in spheroids. We thank the predoctoral i-PFIS IIS-enterprise contract in science and technologies in health granted by the Institute of Health Carlos III (ISCiii; IFI18/00014; to E.N.-V.); the ISCiii (PI16/00090 and PI19/01266), the Andalusian Ministry of Health (PI-0198-2016), the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd) founded by the ISCiii and co-financed by European Development Regional Fund “A way to achieve Europe ” (ERDF) (to J.M.), and ISCiii (PI19/00838) and Valencian Ministry of Education , Culture and Sports (PROMETEO/2019/027) (to V.M.V.) for their financial support .
DS RISalud
RD Aug 21, 2025