title: Emetine dihydrochloride: a novel therapy for bladder cancer.
abstract: OBJECTIVE
  Current cisplatin based therapies for stage IV bladder cancer show 4% to 20% 5-year survival, underscoring the need to develop novel therapies for these patients. In the 1970s the natural alkaloid emetine dihydrochloride demonstrated modest anticancer efficacy as a single agent in clinical trials but this was not pursued. Groups recently reported that emetine induced apoptosis in leukemia cell lines, which was enhanced by cisplatin. We determined the antiproliferative effects of emetine with and without cisplatin in bladder cancer cells.
  
  
  METHODS
  Human bladder cancer cell lines and normal human urothelial cell cultures were treated with emetine and/or cisplatin. We measured cell proliferation and evaluated synergy using the Chou-Talalay method. The combination index was calculated. Cell cycle analysis was done and caspase activation was evaluated to assess growth arrest and apoptosis.
  
  
  RESULTS
  Emetine and cisplatin individually inhibited bladder cancer cell proliferation. When combined, emetine and cisplatin acted synergistically to inhibit tumor cell proliferation with combination index values reflecting moderate to strong synergy. Normal urothelial cells were relatively resistant to this treatment. Emetine alone and combined with cisplatin appeared to primarily induce tumor cell growth arrest and not apoptosis.
  
  
  CONCLUSIONS
  To our knowledge this study demonstrates for the first time that emetine has in vitro antiproliferative activity against bladder cancer cell lines at nanomolar concentrations but little effect on normal urothelial cells. Moreover, emetine and cisplatin worked synergistically to inhibit tumor cell proliferation. Results suggest that combined emetine and cisplatin based chemotherapy may benefit patients with bladder cancer.
authors.affiliation: Department of Pathology, Loyola University Chicago, Maywood, Illinois; Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois. Electronic address: kforema@lumc.edu.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Foreman
authors.affiliation: Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois.
authors.forename: John N
authors.initials: JN
authors.lastname: Jesse
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, Illinois; Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, Illinois; Department of Urology, Loyola University Chicago, Maywood, Illinois; Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois. Electronic address: gogupta@lumc.edu.
authors.forename: Gopal N
authors.initials: GN
authors.lastname: Gupta
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004640:Emetine / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D019459:Urothelium / Q000166:cytology
chemical_list: D000970:Antineoplastic Agents; D011500:Protein Synthesis Inhibitors; D053148:Caspase 3; D053181:Caspase 8; D002945:Cisplatin; D004640:Emetine
keywords: 50% inhibitory concentration; ABC; CI; FBS; FITC; HIF; IC(50); PI; adenosine triphosphate binding cassette; carcinoma; cisplatin; combination index; emetine; fetal bovine serum; fluorescein isothiocyanate; hypoxia-inducible factor; propidium iodide; urinary bladder; urothelium