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.

Significance: 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.

Keywords: Digoxin; cohort; cytotoxicity; prostate cancer; risk; transdisciplinary.

Figure 1

Potency of prostate cancer cell growth inhibition of the 38 FDA-approved or clinically used compounds emerging from the primary screen. Shown are results from the secondary screen for these compounds. The 38 drugs are categorized as known anti-neoplastic or non-antineoplastic drugs based on their known clinical indications. The IC₅₀ determined for each drug and each cell line in the secondary screen are color scaled as shown. Non-antineoplastic drugs are arranged by order of mean potency across the six prostate cancer cell lines.

Figure 2

Association between duration of digoxin use during the study period and prostate cancer risk, 47,884 men in the Health Professionals Follow-up Study, 1986–2006.