title: FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft.
abstract: BACKGROUND
  A unique immunosuppressant, FTY720, selectively induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. The potential that this unique mechanism could provide anticancer potential by inducing apoptosis in the human renal cancer cell line, ACHN, which is resistant to cisplatin, and its molecular pathway was investigated.
  
  
  METHODS
  The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and flow cytometry. Apoptosis assay, including TUNEL staining, electron microscopy and DNA electrophoresis, was performed and the molecular pathway of FTY720 was evaluated by real time RT-PCR and Western blot. The in vivo effect of FTY720 was evaluated using a murine zenograft model.
  
  
  RESULTS
  The susceptibility to FTY720 was significantly higher in ACHN cancer cells than in normal renal tubular cells (HK-2) at a concentration of less than 30 microM, while the susceptibility to cisplatin was even higher in HK-2 than in ACHN. Cancer cells treated with FTY720 showed findings typical of apoptosis with highly condensed nuclear chromatin and fragmented nuclei. The molecular analysis revealed that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway, and that inhibition of extracellular signal-regulated kinase (ERK) activity was involved in its underlying mechanism of action. FTY720 treatment significantly prevented in vivo tumor growth without any severe adverse reactions, while cisplatin treatment did not inhibit tumor growth despite exhibiting severe side-effects.
  
  
  CONCLUSIONS
  FTY720 may be a promising candidate for a new anticancer therapy of renal cancer.
authors.affiliation: Department of Urology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Ubai
authors.forename: Haruhito
authors.initials: H
authors.lastname: Azuma
authors.forename: Yatsugu
authors.initials: Y
authors.lastname: Kotake
authors.forename: Teruo
authors.initials: T
authors.lastname: Inamoto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takahara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ito
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kiyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horie
authors.forename: Satoru
authors.initials: S
authors.lastname: Muto
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
authors.forename: Yoji
authors.initials: Y
authors.lastname: Katsuoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000633:toxicity; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009392:Nephrectomy; D011409:Propylene Glycols / Q000494:pharmacology* / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053181:Caspase 8; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002945:Cisplatin