title: Sunitinib enhances antitumor effects against chemotherapy-resistant             bladder cancer through suppression of ERK1/2 phosphorylation.
abstract: Bladder cancer patients who are refractory to chemotherapy have a poor prognosis.             Furthermore, additional chemotherapies provide little benefit to patients who             have relapsed after an initial response. Recently, it was reported that several             molecular pathways are implicated in bladder carcinogenesis, including the epidermal             growth factor receptor (EGFR) pathway, the vascular endothelial growth factor             (VEGF) pathway and the Ras-MAPK pathway. We hypothesized that sunitinib would             be effective in bladder cancer as it is an oral inhibitor of multiple receptor             tyrosine kinases, including VEGF receptors, platelet derived growth factor (PDGF)             receptors and stem cell factor receptor (c-KIT), and is a standard first-line             treatment of advanced clear cell renal carcinoma. In the present study, the antiproliferative             effects of sunitinib were clearly demonstrated in KK47, KK47/DDP20 and KK47/ADR             cell lines in vitro due to the suppression of ERK1/2 phosphorylation. In a mouse             model, the antitumor effects of sunitinib were again clearly seen. Also, treatment             with sunitinib decreased the abundance of regulatory T cells (Tregs). However,             cytotoxic T lymphocyte (CTL) activity was not induced sufficiently as compared             with an IFN-α-treated group. Our results suggested that sunitinib was effective             in chemotherapy-resistant bladder cancer patients. On the other hand, these findings             provided the rationale for combination therapy with sunitinib and immune-based             cancer therapy for advanced malignancies to prevent the occurrence of rebound             phenomena.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu                     University, Fukuoka, Japan.
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Eto
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kuroiwa
authors.forename: Momoe
authors.initials: M
authors.lastname: Itsumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077210:Sunitinib