Antiarrhythmic drug digoxin has been reported to have apoptosis-inducing and cytotoxic effects on prostate cancer cells. We evaluated the association between antiarrhythmic drug use and prostate cancer risk in a population-based case-control study. The study included all new prostate cancer cases diagnosed in Finland during 1995-2002 and matched controls (24,657 casecontrol pairs) obtained from the Finnish Cancer Registry and the Population Register Center, respectively. Information on antiarrhythmic drug purchases was obtained from national prescription database. Multivariable-adjusted conditional logistic regression model was used for data analysis. Compared to never-users of antiarrhythmic drugs, we found no significant association between digoxin use and prostate cancer risk overall [odds ratio (OR) 0.95, 95% confidence interval (CI): 0.89-1.01] or for advanced prostate cancer risk (OR: 0.90, 95% CI: 0.77-1.05). The result was similar also for other antiarrhythmic drugs, with the exception of sotalol, users of which had decreased risk of advanced prostate cancer (OR: 0.73, 95% CI: 0.56-0.96). Also the overall prostate cancer risk decreased by duration of sotalol use (p for trend 0.038). We show that digoxin or other common antiarrhythmic drugs generally do not associate with prostate cancer risk at population level during maximum followup of eight years. However, we cannot rule out longer term protective effects of digoxin. K1 -channel blocker sotalol shows some promise as prostate cancer preventing agent. However, findings need to be confirmed in further studies.Prostate cancer is the most common malignancy among men in most countries. 1 Despite being a major public health problem, its etiology is still not well-known. A deeper knowledge of the risk factors is needed for prevention and better treatment of the condition.Digoxin, a commonly used antiarrhythmic agent, inhibits prostate cancer cell growth by increasing apoptosis.2,3 The mechanism of action for cardiac glycosides such as digoxin involves inhibition of the plasma membrane Na1/K1-ATPase, leading to changes in intracellular K1-and Ca21-concentrations. The apoptosis-inducing effect of digoxin has been proposed to be caused by increased Ca21-uptake in prostate cancer cells, 2,3 leading to changes in activity of cyclin-dependent kinase Cdk5, p35 cleavage and p25 formation. 4 Cardiac glycosides also decrease prostate specific antigen (PSA) secretion in prostate cancer cells. 5 In a mouse model digoxin treatment caused decreased blood vessel density and inhibition of HIF-1a expression in castrationresistant xenograft tumors, but no reduction in tumor volume. 6On the other hand, digoxin possesses estrogen-mimicking effects, and its use is associated with an increased incidence of breast and uterine cancer.7 This would provide another plausible mechanism for prostate cancer inhibiting effects.Recently, a novel two-stage study confirmed, at the first stage, the cytotoxic effects of digoxin against prostate cancer cells in an in vitro cytotoxicity screen.8 ...

Digoxin or other antiarrhythmic drugs are not associated with any clear decrease in prostate cancer risk. However, digoxin might have a benefit in long-term use by reducing risk of high-grade disease. Further research will be needed to evaluate possible effects on prostate cancer survival.

Background:Protective effects have been suggested for digoxin against prostate cancer risk. However, few studies have evaluated the possible effects on prostate cancer-specific survival. We studied the association between use of digoxin or beta-blocker sotalol and prostate cancer-specific survival as compared with users of other antiarrhythmic drugs in a retrospective cohort study.Methods:Our study population consisted of 6537 prostate cancer cases from the Finnish Randomized Study of Screening for Prostate Cancer diagnosed during 1996–2009 (485 digoxin users). The median exposure for digoxin was 480 DDDs (interquartile range 100–1400 DDDs). During a median follow-up of 7.5 years after diagnosis, 617 men (48 digoxin users) died of prostate cancer. We collected information on antiarrhythmic drug purchases from the national prescription database. Both prediagnostic and postdiagnostic drug usages were analysed using the Cox regression method.Results:No association was found for prostate cancer death with digoxin usage before (HR 1.00, 95% CI 0.56–1.80) or after (HR 0.81, 95% CI 0.43–1.51) prostate cancer diagnosis. The results were also comparable for sotalol and antiarrhythmic drugs in general. Among men not receiving hormonal therapy, prediagnostic digoxin usage was associated with prolonged prostate cancer survival (HR 0.20, 95% CI 0.05–0.86).Conclusions:No general protective effects against prostate cancer were observed for digoxin or sotalol usage.

In-vitro studies have suggested that the antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study. The study population consists of 78,615 men originally identified for the Finnish Randomized Study of Screening for Prostate Cancer. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used the Cox regression method to analyze separately overall cancer mortality and mortality from the most common types of cancer. During the median follow-up of 17.0 years after the baseline 28,936 (36.8%) men died, of these 8,889 due to cancer. 9,023 men (11.5%) had used antiarrhythmic drugs. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.43, 95% CI 1.34–1.53). Similar results were observed separately for digoxin and for sotalol. However, the risk associations disappeared in long-term use and were modified by background co-morbidities. All in all, cancer mortality was elevated among antiarrhythmic drug users. This association is probably non-causal as it was related to short-term use and disappeared in long-term use. Our results do not support the anticancer effects of digoxin or any other antiarrhythmic drug.

Introduction: In-vitro studies have suggested that antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. A non-selective beta-blocker sotalol has similar effect on K+-channels. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study. Materials and methods: The study population consists of 78,615 men originally identified for the Finnish Randomized Study for Screening of Prostate Cancer. Men were 55-69 years old at baseline. Prevalent prostate cancer cases were excluded; no exclusions were made based on other cancer types. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used Cox regression method to analyze the overall cancer mortality and individually mortality from the most common causes of cancer death. Results: A total of 8,064 men (10.3%) had used antiarrhythmic drugs. Of these 5,668 had used digoxin and 2,540 had used sotalol. During the median follow-up of 16.9 years after baseline 26,790 (34.1%) men died, of these 8,225 (30.7% of deaths) due to cancer. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.25, 95% CI 1.12-1.40). Similar results were observed for digoxin (HR 1.44, 95% CI 1.26-1.63) but not for sotalol (HR 0.92, 95% CI 0.68-1.24). Furthermore, the antiarrhythmic drug use was associated with elevated risk of lung-cancer death (HR 1.76 95% CI 1.46-2.14). However, the risk associations disappeared in long-term use. When we restricted the analysis to cancer cases only, no differences were observed in survival after the cancer diagnosis for any cancer type. Conclusion: Cancer mortality was elevated among users of antiarrhythmic drugs compared to non-users. This association is probably due to the differences between users and non-users as it was related to short-term use, and disappeared in long-term use. Use of digoxin or sotalol was not associated with improved cancer-specific survival. Citation Format: Kalle J. Kaapu, Teemu Murtola, Kirsi Talala, Kimmo Taari, Teuvo Tammela, Anssi Auvinen. Cancer mortality by antiarrhythmic drug use in a population-based cohort of Finnish men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3290. doi:10.1158/1538-7445.AM2017-3290