title: Inhibition of heme oxygenase-1 enhances the cytotoxic effect of gemcitabine in urothelial cancer cells.
abstract: BACKGROUND
  Elevated heme oxygenase-1 (HO-1) is associated with resistance to chemo- and radiotherapy through anti-apoptotic function. The present study evaluated whether the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), enhances the cytotoxic effect of gemcitabine in urothelial carcinoma (UC).
  
  
  METHODS
  The in vitro cytotoxic effect of combination treatment of gemcitabine and ZnPP on UC cells was examined. The in vivo growth inhibitory effects of intraperitoneal administration of gemcitabine and/or ZnPP on mouse subcutaneous tumours were examined. The apoptotic changes were analysed with the detection of DNA fragmentation and cleaved caspase-3.
  
  
  RESULTS
  HO-1 was up-regulated by both gemcitabine and irradiation treatment in vitro. ZnPP sensitised the UC cells to both therapies. Enhanced apoptosis was induced by the ZnPP combined with gemicitabine. ZnPP enhanced the antitumour effect of gemcitabine in vivo along with decreased numbers of proliferating cells and increased numbers of apoptotic cells.
  
  
  CONCLUSIONS
  These findings suggest that ZnPP combined with gemcitabine or irradiation therapy may be an effective therapeutic modality for UC patients.
authors.affiliation: Department of Urology, Nara Medical University, Nara, 634-8522, Japan. mm-ulo@naramed-u.ac.jp
authors.forename: Makito
authors.initials: M
authors.lastname: Miyake
authors.forename: Kiyohide
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Anai
authors.forename: Sayuri
authors.initials: S
authors.lastname: Ohnishi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nakai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tomioka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ikeda
authors.forename: Eijiro
authors.initials: E
authors.lastname: Okajima
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Tanaka
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirao
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011524:Protoporphyrins / Q000494:pharmacology; D011836:Radiation Tolerance; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D011524:Protoporphyrins; D003841:Deoxycytidine; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1; D000093542:Gemcitabine