232 CHARACTERIZATION OF MECHANISM MEDIATING ACQUISITION OF RESISTANCE TO SUNITINIB IN HUMAN RENAL CELL CARCINOMA ACHN CELLS

JOURNAL OF UROLOGY(2011)

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You have accessJournal of UrologyKidney Cancer: Basic Research1 Apr 2011232 CHARACTERIZATION OF MECHANISM MEDIATING ACQUISITION OF RESISTANCE TO SUNITINIB IN HUMAN RENAL CELL CARCINOMA ACHN CELLS Iori Sakai, Hideaki Miyake, Sadao Kamidono, and Masato Fujisawa Iori SakaiIori Sakai Kobe, Japan More articles by this author , Hideaki MiyakeHideaki Miyake Kobe, Japan More articles by this author , Sadao KamidonoSadao Kamidono Kobe, Japan More articles by this author , and Masato FujisawaMasato Fujisawa Kobe, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.301AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Sunitinib, a novel orally available inhibitor of multiple kinases, has been shown to have encouraging anti-tumor activity against advanced renal cell carcinoma (RCC); however, acquired resistance to sunitinib invariably develops in RCC patients who initially respond to treatment with sunitinib, but whose cancer then progress. The objectives of this study were to establish RCC cell line resistant to sunitinib and to characterize the mechanism underlying the acquisition of this resistant mechanism. METHODS A human RCC cell line, ACHN, was continuously exposed to increasing doses of sunitinib in vitro, and a sunitinib-resistant cell line ACHN/R was developed. Changes in the phenotype in ACHN/R cells before and after sunitinib treatment were compared with those in parental ACHN (ACHN/P) cells. RESULTS The IC50 of sunitinib in ACHN/R was approximately 5-fold higher than that in ACHN/P, while there was no significant difference in the growth between ACHN/P and ACHN/R cells when cultured in the standard medium without sunitinib. Sensitivities of ACHN/R to cisplatin, docetaxel and sorafenib were significantly lower than those of ACHN/P; however, there were no significant differences in those to temsirolimus and everolimus between ACHN/P and ACHN/R. Despite the lack of significant differences in the expression levels of MDR1, phosphorylated p44/42 MAPK, Akt and STAT3, VEGF, IL-8, PDGF-AB and -BB before sunitinib treatment, following the administration of sunitinib, expression levels of MDR1, phosphorylated p44/42 MAPK, Akt, VEGF and PDGF-AB were significantly inhibited compared with those in ACHN/R. Similarly, receptor tyrosine kinase assay showed that treatment of ACHN/P with sunitinib resulted in the marked downregulation of phosphorylated of BMX, Htk, MATK, RET, TNK1 and TXK compared with that of ACHN/R. Furthermore, additional treatment with LY294002, a specific inhibitor of the Akt signaling pathway, significantly increased the sensitivity of ACHN/R, but not that of ACHN/P, to sunitinib. CONCLUSIONS These findings suggest that the maintained phosphorylation of several types of protein kinases as well as production of angiogenic factors during the treatment with sunitinib may be involved in the acquisition of resistant phenotype in RCC cells to this agent; therefore, it would be worthy to further investigate the significance of agents inactivating either protein kinases or angiogenic factors, such as LY294002, as possible candidates for overcoming resistance to sunitinib in patients with RCC. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e94-e95 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.Metrics Author Information Iori Sakai Kobe, Japan More articles by this author Hideaki Miyake Kobe, Japan More articles by this author Sadao Kamidono Kobe, Japan More articles by this author Masato Fujisawa Kobe, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
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Key words
renal cell carcinoma,sunitinib,human renal cell
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