title: Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type 1 receptor in bladder cancer.
abstract: BACKGROUND
  We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type 1 receptor (AT1R) after the development of acquired platinum resistance in bladder cancer.
  
  
  METHODS
  Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months.
  
  
  RESULTS
  Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher AT1R expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased AT1R expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of AT1R blockade at suppressing the growth of platinum-resistant xenograft model.
  
  
  CONCLUSIONS
  Our findings indicate a new molecular mechanism for upregulated AT1R signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of AT1R blockade for platinum-resistant bladder cancers.
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
authors.forename: A
authors.initials: A
authors.lastname: Miyajima
authors.forename: T
authors.initials: T
authors.lastname: Kosaka
authors.forename: Y
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: S
authors.initials: S
authors.lastname: Shirotake
authors.forename: H
authors.initials: H
authors.lastname: Shirakawa
authors.forename: E
authors.initials: E
authors.lastname: Kikuchi
authors.forename: M
authors.initials: M
authors.lastname: Oya
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D000077553:Edaravone; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis*; D001749:Urinary Bladder Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D002945:Cisplatin; D000077553:Edaravone; D000983:Antipyrine