{"doi":"10.1016/j.juro.2014.02.1045","title":"MP35-02 MOLECULAR MECHANISM MEDIATING CYTOTOXIC ACTIVITY OF AXITINIB IN SUNITINIB-RESISTANT HUMAN RENAL CELL CARCINOMA CELLS","abstract":null,"journal":"Journal of Urology","year":2014,"id":664608,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1640306,"name":"Hideaki Miyake","orcid":null,"position":1,"is_corresponding":false},{"id":1657706,"name":"Masato Fujisawa","orcid":null,"position":2,"is_corresponding":false},{"id":1735374,"name":"Akira Miyazaki","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"MP35-02 MOLECULAR MECHANISM MEDIATING CYTOTOXIC ACTIVITY OF AXITINIB IN SUNITINIB-RESISTANT HUMAN RENAL CELL CARCINOMA CELLS","abstract":"You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2014MP35-02 MOLECULAR MECHANISM MEDIATING CYTOTOXIC ACTIVITY OF AXITINIB IN SUNITINIB-RESISTANT HUMAN RENAL CELL CARCINOMA CELLS Akira Miyazaki, Hideaki Miyake, and Masato Fujisawa Akira MiyazakiAkira Miyazaki More articles by this author , Hideaki MiyakeHideaki Miyake More articles by this author , and Masato FujisawaMasato Fujisawa More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1045AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although axitinib and sunitinib are shown to exert antitumor activity against renal cell carcinoma (RCC) based on common mechanism characterized by the inhibition of tumor cell proliferation as well as angiogenesis through the inactivation of receptor tyrosine kinases, it has been well documented that axitinib still have a powerful therapeutic activity in patients with RCC who acquired resistance to sunitinib. The objective of this study was to clarify molecular mechanism mediating cytotoxic activity of axitinib in sunitinib-resistant human RCC cells. METHODS A parental human RCC cell line, ACHN (ACHN/P), was continuously exposed to increasing doses of sunitinib, and a cell line resistant to sunitinib (ACHN/R), showing an approximately 5-fold higher IC50 than that of ACHN/P, was developed. Differences in molecular phenotypes following treatment with sunitinib or axitinib between these two cell lines were compared. RESULTS ACHN/R appeared to acquire significant cross resistance to another potential tyrosine kinase inhibitor, sorafenib; however, there were no significant differences in sensitivities to axitinib in addition to the Mammalian target of rapamycin inhibitors, temsirolimus and everolimus, between ACHN/P and ACHN/R. In ACHN/P, both sunitinib and axitinib markedly inhibited the expression levels of phosphorylated Akt, p44/42 mitogen activated protein kinase (MAPK) and vascular endothelial growth factor receptor-2 (VEGFR-2). In ACHN/R, however, phosphorylation of Akt, p44/42 MAPK and VEGFR-2 were maintained following treatment with sunitinib, whereas treatment with axitinib resulted in the marked down-regulation of both phosphorylated p44/42 MAPK and VEGFR-2, but not that of Akt. Furthermore, additional treatment with LY294002, a specific inhibitor of AKT, significantly increased the sensitivity of ACHN/R to axitinib, but not that of ACHN/P. In vivo growth of ACHN/R in nude mice following treatment with axitinib was also significantly suppressed compared with that following treatment with sunitinib. CONCLUSIONS These findings suggest that 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 following treatment with sunitinib, and that combined administration of a specific inhibitor of Akt may further enhance the cytotoxic effect of axitinib on sunitinib-resistant human RCC cells. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e370-e371 Advertisement Copyright & Permissions© 2014Metrics Author Information Akira Miyazaki More articles by this author Hideaki Miyake More articles by this author Masato Fujisawa More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19162232","pmcid":null,"openalex_id":"https://openalex.org/W4230041281","authors":[],"funders":[],"total_grants":0,"fwci":0.0,"citation_percentile":0.44534969,"influential_citations":0,"citation_trend":[],"oa_status":"closed","license":"https://www.elsevier.com/tdm/userlicense/1.0/","oa_locations":[{"url":"https://api.elsevier.com/content/article/PII:S0022534714013032?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0022534714013032?httpAccept=text/plain","host_type":"publisher"},{"url":"http://www.jurology.com/doi/pdf/10.1016/j.juro.2014.02.1045","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.juro.2014.02.1045","host_type":"journal"}],"fields_of_study":["Advanced Breast Cancer Therapies","Renal cell carcinoma treatment"],"mesh_terms":[],"keywords":["Axitinib","Sunitinib","Medicine","Cancer research","Renal cell carcinoma","Cytotoxic T cell","Tyrosine kinase","Pharmacology","Cell culture","Tyrosine-kinase inhibitor","Receptor tyrosine kinase","Sorafenib","Internal medicine","Receptor","Cancer","Biology","In vitro","Biochemistry"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-13T03:30:30.052415Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}