A Miyazaki1, H Miyake2, M Fujisawa1. 1. Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. 2. Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. hideakimiyake@hotmail.com.
Abstract
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 IC50 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.
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 humanRCC 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 IC50 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.
Authors: Shih-Chi Su; Xiaoxiao Hu; Patrick A Kenney; Megan M Merrill; Kara N Babaian; Xiu-Ying Zhang; Tapati Maity; Shun-Fa Yang; Xin Lin; Christopher G Wood Journal: Clin Cancer Res Date: 2013-10-11 Impact factor: 12.531
Authors: Brian I Rini; Bernard Escudier; Piotr Tomczak; Andrey Kaprin; Cezary Szczylik; Thomas E Hutson; M Dror Michaelson; Vera A Gorbunova; Martin E Gore; Igor G Rusakov; Sylvie Negrier; Yen-Chuan Ou; Daniel Castellano; Ho Yeong Lim; Hirotsugu Uemura; Jamal Tarazi; David Cella; Connie Chen; Brad Rosbrook; Sinil Kim; Robert J Motzer Journal: Lancet Date: 2011-11-04 Impact factor: 79.321