Molecular mechanism mediating cytotoxic activity of axitinib in sunitinib-resistant human renal cell carcinoma cells

• Published in: Clinical & translational oncology Vol. 18; no. 9; pp. 893 - 900
• Main Authors: Miyazaki, A., Miyake, H., Fujisawa, M.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.09.2016
• Subjects: Animals; Antineoplastic Agents - pharmacology; Blotting, Western; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Cell Proliferation - genetics; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enzyme-Linked Immunosorbent Assay; Humans; Imidazoles - pharmacology; Immunohistochemistry; Indazoles - pharmacology; Indoles - pharmacology; Kidney Neoplasms - pathology; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 3 - genetics; Oncology; Protein Kinase Inhibitors - pharmacology; Pyrroles - pharmacology; Research Article; Vascular Endothelial Growth Factor Receptor-2 - genetics; Xenograft Model Antitumor Assays; Axitinib; Sunitinib; p44/42 Mitogen-activated protein kinase; Vascular endothelial growth factor receptor-2; Renal cell carcinoma
• ISSN: 1699-048X; 1699-3055
• DOI: 10.1007/s12094-015-1457-x

Purpose This study aimed to clarify the molecular mechanism mediating the cytotoxicity of axitinib, a selective inhibitor of the vascular endothelial growth factor receptor (VEGFR), in sunitinib-resistant renal cell carcinoma (RCC). Methods In our previous study (Sakai et al. in BJU Int 112:E211–E220, 2013 ), a human RCC cell line, ACHN, resistant to sunitinib (ACHN/R), was developed from a parental cell line (ACHN/P). Differences in molecular phenotypes following treatment with sunitinib or axitinib between these two cell lines were compared. Results ACHN/R showed an approximately fivefold higher IC 50 of sunitinib than ACHN/P; however, there was no significant difference in the sensitivity to axitinib between these two cell lines. In ACHN/R, despite the lack of a difference in the phosphorylated (p)-Akt or STAT-3 expression between treatment with sunitinib and axitinib, the expression of p-p44/42 mitogen-activated protein kinase (MAPK) and p-VEGFR-2 after treatment with axitinib was markedly down-regulated compared with those after treatment with sunitinib. Furthermore, additional treatment of ACHN/R with an inhibitor of MAPK kinase significantly enhanced the cytotoxic activity of sunitinib, but not that of axitinib. In vivo growth of ACHN/R in nude mice after treatment with axitinib was significantly inhibited compared with that following treatment with sunitinib, accompanying the marked inhibition of angiogenesis. Conclusions Antitumor activity of axitinib in RCC cells even after the acquisition of resistance to sunitinib could be explained, at least in part, by the inactivation of p44/42 MAPK and VEGFR-2, which were persistently phosphorylated in sunitinib-resistant RCC cells under treatment with sunitinib.