title: A novel two-stage, transdisciplinary study identifies digoxin as a possible drug for prostate cancer treatment.
abstract: Identification of novel indications for commonly prescribed drugs could accelerate translation of therapies. We investigated whether any clinically-used drugs might have utility for treating prostate cancer by coupling an efficient, high-throughput laboratory-based screen and a large, prospective cohort study. In stage 1, we conducted an in vitro prostate cancer cell cytotoxicity screen of 3,187 compounds. Digoxin emerged as the leading candidate given its potency in inhibiting proliferation in vitro (mean IC₅₀=163 nM) and common use. In stage 2, we evaluated the association between the leading candidate drug from stage 1 and prostate cancer risk in 47,884 men followed 1986-2006. Regular digoxin users (versus nonusers: RR=0.76, 95% CI 0.61-0.95), especially users for ≥ 10 years (RR=0.54, 95% CI 0.37-0.79, P-trend<0.001), had a lower prostate cancer risk. Digoxin was highly potent in inhibiting prostate cancer cell growth in vitro and its use was associated with a 25% lower prostate cancer risk.
  
  
  CONCLUSIONS
  Our two-stage transdisciplinary approach for drug repositioning provides compelling justification for further mechanistic and possibly clinical testing of the leading nonchemotherapy candidate, digoxin, a cardiac glycoside, as a drug for prostate cancer treatment. Perhaps of equal importance, our study illustrates the power of the transdisciplinary approach in translational cancer research. By coupling laboratory and epidemiologic methods and thinking, we reduced the probability of identifying false-positive candidate drugs for the next steps in testing.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. eplatz@jhsph.edu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Platz
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Yegnasubramanian
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Chong
authors.forename: Joong Sup
authors.initials: JS
authors.lastname: Shim
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Kenfield
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Walter C
authors.initials: WC
authors.lastname: Willett
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: William G
authors.initials: WG
authors.lastname: Nelson
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D004077:Digoxin / Q000494:pharmacology*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012307:Risk Factors; D011795:Surveys and Questionnaires
chemical_list: D004077:Digoxin