digoxin and Prostatic-Neoplasms

Digoxin, a commonly used drug for congestive heart failure and cardiac arrhythmias, has been reported to exert cytotoxic and apoptosis-inducing effects on prostate cancer (PCa) cells. In this study, we aimed to perform a pooled analysis to summarise all the evidence related to the effects of digoxin on PCa development. Four electronic databases were systematically searched to filter the eligible studies. The hazard ratio (HR) with its 95% confidence interval (CI) was calculated. This study was registered on PROSPERO (ID: CRD42021226885). Ten clinical studies with a total of 108,444 participants (15,835 individuals were digoxin users) were included. The pooled result from 6 included studies demonstrated that digoxin usage was correlated with a significant decrease in PCa risk (adjusted RR = 0.892, 95% CI: 0.799-0.997, p = .044) when compared with the nonusers. Synthetic result of 4 eligible studies revealed that digoxin significantly correlated with higher prostate cancer-specific mortality than the controls (adjusted HR = 1.142, 95% CI: 1.005-1.297). No statistical heterogeneity was detected during this analysis (all I

Topics: Digoxin; Humans; Incidence; Male; Pharmaceutical Preparations; Prostatic Neoplasms

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.. 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.. 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).. No general protective effects against prostate cancer were observed for digoxin or sotalol usage.

Topics: Anti-Arrhythmia Agents; Digoxin; Finland; Humans; Male; Mass Screening; Prostatic Neoplasms; Retrospective Studies; Survival Analysis

CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) is a potential target for prostate cancer treatment. Herein, we report the structural optimization of a series of 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led to compound

Topics: Animals; Antineoplastic Agents; Caco-2 Cells; Cell Line, Tumor; CREB-Binding Protein; Drug Design; Humans; Indolizidines; Male; Mice; Mice, SCID; Microsomes, Liver; Models, Molecular; Molecular Docking Simulation; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

Topics: Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins; Cell Line, Tumor; DNA-Binding Proteins; Humans; Male; Prostatic Neoplasms; Protein Domains

In vitro studies have confirmed that cardiac glycosides can induce apoptosis in both hormone-dependent and -independent prostate cancer (PCa) cell lines. The aim of this study was to investigate the incidence of PCa among patients treated with and without digoxin using a nationwide population-based database in Taiwan.. We retrieved data of men aged 30 years or older who were newly diagnosed with heart failure between January 1998 and December 2003 from the National Health Insurance program database in Taiwan. We divided the patients into digoxin users and non-digoxin users. Kaplan-Meier curves and Cox proportional hazard analysis were used to examine the risk of subsequent PCa between the digoxin and non-digoxin groups.. The mean ± SD follow-up (years) periods in the digoxin and non-digoxin groups were 8.6 ± 1.78 and 8.3 ± 1.75, respectively. The cumulative incidence of PCa during the follow-up period was 3.5% (147/4233) in the non-digoxin group compared with 3.0% (65/2154) in the digoxin group. The log-rank test revealed that the digoxin group had a similar incidence of PCa to the non-digoxin group (p = 0.18). After adjusting for age, benign prostatic hyperplasia, and comorbidities, Cox proportional hazard regression analysis showed that digoxin was associated with a significantly decreased risk of developing PCa (hazard ratio, 0.74; 95% CI, 0.548-0.993; p = 0.045). Moreover, logistic regression analysis showed that the risk of PCa decreased with a longer duration of digoxin use during the study period compared to those who had never used digoxin (p = 0.043).. The cardiac glycoside digoxin had significant effects on reducing the incidence of PCa in a time-dependent manner. Our findings may imply the potential application of cardiac glycosides in the prevention and management of PCa.

Topics: Aged; Digoxin; Humans; Incidence; Logistic Models; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms

Topics: Aged, 80 and over; Antineoplastic Agents; Benzamides; Cardiovascular Agents; Digoxin; Drug Monitoring; Heart Diseases; Humans; Immunoassay; Luminescent Measurements; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms

Corchorusoside C (1), isolated from Streptocaulon juventas collected in Vietnam, was found to be nontoxic in a zebrafish ( Danio rerio) model and to induce cytotoxicity in several cancer cell lines with notable selective activity against prostate DU-145 cancer cells (IC

Topics: Animals; Antineoplastic Agents, Phytogenic; Apocynaceae; Apoptosis; Caspases; Cell Line, Tumor; Humans; I-kappa B Kinase; Male; Molecular Structure; Poly (ADP-Ribose) Polymerase-1; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrans; Vietnam; Zebrafish

Topics: Aged; Atrial Fibrillation; Benzamides; Digoxin; Drug Interactions; Drug Overdose; Drug Substitution; Hematemesis; Humans; International Normalized Ratio; Male; Nitriles; Phenindione; Phenylthiohydantoin; Polypharmacy; Prostatic Neoplasms; Tinzaparin

Long-term usage of the antiarrhythmic drug digoxin has been connected to lowered risk of prostate cancer. A recent study has suggested that beta-blockers might also have similar risk-decreasing effects. We evaluated the association between use of digoxin, beta-blocker sotalol, and other antiarrhythmic drugs and prostate cancer risk in a retrospective cohort study.. Our study population consisted of men in the Finnish Prostate Cancer Screening Trial during 1996-2012 (n = 78,615). During median follow-up of 12 years, 6,639 prostate cancer cases were diagnosed. The national prescription database was the source of the information of antiarrhythmic drug purchases. Data were analyzed using Cox regression method with medication use as a time-dependent variable.. No association was found for overall prostate cancer risk with antiarrhythmic drug use (HR 1.05 95% CI 0.94-1.18). Neither sotalol (HR 0.97 95% CI 0.76-1.24) nor digoxin (HR 1.01 95% CI 0.87-1.16) users had a decreased risk of prostate cancer. Similar results were obtained for high-grade (Gleason 7-10) and metastatic prostate cancer. Nevertheless, the risk estimates for Gleason 7-10 prostate cancer tended to decrease by duration of digoxin use (p for trend = 0.052), suggesting that the drug may reduce the risk in long-term usage (HR 0.71, 95% CI 0.49-1.03). In analysis stratified by screening trial arm, the protective association against Gleason 7-10 disease was observed only in the screening arm (HR 0.31, 95% CI 0.12-0.84 for men who had used digoxin for 5 years or longer).. 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.

Topics: Adrenergic beta-Antagonists; Aged; Anti-Arrhythmia Agents; Cohort Studies; Digoxin; Finland; Humans; Male; Middle Aged; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Protective Factors; Retrospective Studies; Sotalol

Preclinical studies have shown that digoxin exerts anticancer effects on different cancer cell lines including prostate cancer. A recent observational study has shown that digoxin use was associated with a 25% reduction in prostate cancer risk. The aim of this study was to investigate whether digoxin use after diagnosis of prostate cancer was associated with decreased prostate cancer-specific mortality.. A cohort of 13 134 patients with prostate cancer newly diagnosed from 1998 to 2009 was identified from English cancer registries and linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify 2010 prostate cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and prostate cancer-specific mortality.. Overall, 701 (5%) patients with prostate cancer used digoxin after diagnosis. Digoxin use was associated with an increase in prostate cancer-specific mortality before adjustment (HR = 1.59; 95% CI 1.32-1.91), but after adjustment for confounders, the association was attenuated (adjusted HR = 1.13; 95% CI 0.93-1.37) and there was no evidence of a dose response.. In this large population-based prostate cancer cohort, there was no evidence of a reduction in prostate cancer-specific mortality with digoxin use after diagnosis. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Anti-Arrhythmia Agents; Cohort Studies; Digoxin; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Male; Proportional Hazards Models; Prostatic Neoplasms; Registries; Survival Rate; Time Factors

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 case-control 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 follow-up of eight years. However, we cannot rule out longer term protective effects of digoxin. K(+) -channel blocker sotalol shows some promise as prostate cancer preventing agent. However, findings need to be confirmed in further studies.

Topics: Anti-Arrhythmia Agents; Case-Control Studies; Digoxin; Finland; Humans; Logistic Models; Male; Potassium Channel Blockers; Prostatic Neoplasms; Sotalol

Topics: Antineoplastic Agents; Breast Neoplasms; Cardiotonic Agents; Digoxin; Female; Humans; Male; Prostatic Neoplasms

To examine the association between digoxin exposure and mortality in men with prostate cancer using linked Irish National Cancer Registry and pharmacy claims data.. Prostate cancer cases were identified from the database and digoxin exposure at prostate cancer diagnosis was identified from prescription claims. Digoxin users were matched to non-users using a propensity score to identify men with similar cardiovascular comorbidity. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the association between digoxin exposure and all-cause and prostate cancer-specific mortality (PCSM). Analyses were repeated in the propensity score-matched cohort. Effect modification of treatment with radiation or androgen-deprivation therapy by digoxin exposure was also assessed.. In all, 5732 men with a prostate cancer diagnosis (2001-2006) were identified (digoxin exposed, 391). The median follow-up was 4.3 years. Digoxin exposure was associated with a small non-significant increase in PCSM in the full cohort (HR 1.13, 95% CI 0.91, 1.42) and the propensity. score-matched cohort (HR 1.17, 95% CI 0.88, 1.57). Adjusted HRs for all-cause mortality were increased for digoxin exposed men (HR 1.24, 95% CI 1.07, 1.43). Interactions with treatments received were not significant.. These results suggest digoxin exposure is not associated with reduced PCSM. Further investigation of other cardiac glycosides that have shown anti-cancer potential may be warranted.

Topics: Adult; Aged; Androgen Antagonists; Anti-Arrhythmia Agents; Biomarkers, Tumor; Cardiotonic Agents; Cardiovascular Diseases; Cause of Death; Cohort Studies; Combined Modality Therapy; Digoxin; Humans; Incidence; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; Survival Analysis; Treatment Outcome

Digoxin is a commonly used medication for heart failure and cardiac arrhythmias that has recently been suggested as a novel chemotherapeutic agent. Preclinical studies of prostate cancer (PCa) have shown anti-tumor activity with digoxin. We explore the relationship between use of digoxin and PCa risk.. Data from a population-based case-control study of incident cases aged 35-74 years at PCa diagnosis in 2002-2005 in King County, Washington were available. Controls were identified by random digit dialing and frequency matched by age. Use of digoxin was determined from in-person questionnaires regarding medical and prescription history. The relationship of digoxin use with PCa risk was evaluated with logistic regression.. One thousand one cases of PCa and 942 controls were analyzed. The prevalence of digoxin use in controls was 2.7%, and use was positively correlated with age. In multivariate analysis adjusting for age, race, PSA screening, and family history of PCa, digoxin use was associated with a reduction in the odds ratio of PCa (OR 0.58, 95% CI: 0.30-1.10). Among those with ≥3 PSA tests over the preceding 5 years (546 cases, 380 controls), digoxin use was associated with a stronger reduction of PCa risk (OR 0.44, 95% CI: 0.20-0.98).. These data indicate digoxin use may be associated with a reduction in risk of PCa. Given the potential mechanisms by which digoxin may exert an anti-neoplastic effect and other recent studies showing a negative association between digoxin use and PCa, further research is warranted.

Topics: Adult; Aged; Cardiovascular Diseases; Case-Control Studies; Digoxin; Humans; Male; Middle Aged; Population Surveillance; Prostatic Neoplasms; Risk Factors

Recent studies suggest a potential application for digoxin in the prevention and/or treatment of prostate cancer. However, the effect of digoxin on androgen receptor (AR)-positive prostate tumor in vivo is not clear. This study is designed to determine if digoxin can inhibit AR-positive xenograft prostate tumors.. Athymic male nude mice were utilized to establish subcutaneous C4-2 castration-resistant prostate tumors. The animals were castrated and then treated with daily intraperitoneal (i.p.) injection of digoxin at 2 mg/kg along with vehicle controls for 7 consecutive days. Tumor growth was determined by measuring tumor volume changes, blood vessel density by immunostaining of CD31, and cell proliferation by BrdU labeling. The expression of HIF-1α in C4-2 tumors was measured by Western blot and real-time RT-PCR.. Digoxin inhibited blood vessel density about fourfold and down-regulated HIF-1α expression at both mRNA and protein levels. However, digoxin did not inhibit C4-2 tumor growth.. Digoxin is a potent inhibitor of HIF-1α signaling pathway and blood vessel formation in C4-2 castration-resistant prostate tumors.

Topics: Angiogenesis Inhibitors; Animals; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Digoxin; Down-Regulation; Drug Administration Schedule; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Injections, Intraperitoneal; Male; Mice; Mice, Nude; Neovascularization, Pathologic; Orchiectomy; Platelet Endothelial Cell Adhesion Molecule-1; Prostatic Neoplasms; Real-Time Polymerase Chain Reaction; Receptors, Androgen; RNA, Messenger; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays

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.. 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.

Topics: Cell Line, Tumor; Cell Proliferation; Cohort Studies; Digoxin; Follow-Up Studies; Humans; Male; Prospective Studies; Prostatic Neoplasms; Risk Factors; Surveys and Questionnaires

We highlight the value of carefully designed observational epidemiologic analyses in translating basic science discoveries to clinical application and in providing the impetus for exploring underlying mechanisms for observed associations. Coupling epidemiologic data with an in vitro screen of commonly used therapeutic agents may identify novel applications for further clinical testing.

Topics: Digoxin; Humans; Male; Prostatic Neoplasms

While cardiac glycosides are the mainstay of congestive heart failure treatment, early studies showed that pharmacological doses of cardiac glycosides inhibited prostate cancer cell line proliferation. We evaluated the mechanisms of cardiac glycosides, including digoxin, digitoxin and ouabain (Sigma®), on prostate specific antigen gene expression in vitro.. We cultured LNCaP cells (ATCC®) and used them to determine the effect of cardiac glycosides on prostate derived Ets factor and prostate specific antigen expression. We determined prostate derived Ets factor and prostate specific antigen expression by reverse transcription-polymerase chain reaction, immunoblot, transient gene expression assay or enzyme-linked immunosorbent assay.. Noncytotoxic doses (100 nM) of cardiac glycosides for 24 hours inhibited prostate specific antigen secretion by LNCaP cells. Reverse transcriptase-polymerase chain reaction and immunoblot revealed that cardiac glycosides significantly down-regulated prostate specific antigen and prostate derived Ets factor expression. Transient gene expression assays showed that prostate derived Ets factor over expression enhanced prostate specific antigen promoter activity. However, prostate specific antigen and prostate derived Ets factor gene promoter activity was attenuated when LNCaP cells were treated with 100 nM cardiac glycosides. When LNCaP cells were treated with 25 nM digitoxin or digoxin for 60 hours, prostate specific antigen secretion decreased by 30%.. Results suggest that cardiac glycoside inhibition of prostate specific antigen gene expression may be caused by the down-regulation of prostate derived Ets factor gene expression. When cells were chronically treated with digoxin or digitoxin at concentrations close to or at therapeutic plasma levels, prostate specific antigen secretion decreased. This phenomenon merits further study to determine whether it occurs in men on cardiac glycoside therapy.

Topics: Cardiac Glycosides; Cardiotonic Agents; Digitoxin; Digoxin; Down-Regulation; Gene Expression Regulation; Humans; Male; Ouabain; Prostate-Specific Antigen; Prostatic Neoplasms; Proto-Oncogene Proteins c-ets; Tumor Cells, Cultured

Cardiac digitalis has been considered to be a treatment for breast cancer. Our previous study indicates that digoxin, one member in digitalis, decreases the proliferation of prostate cancer cells, but the mechanisms remain unclear. In the present study, Ca(2+) proved to be an important factor in digoxin-triggered prostate cancer cell death. Because cyclin-dependent kinase (Cdk)5 and p35 cleavage (p25 formation) have been reported to be targets of intracellular Ca(2+), and subsequently correlated to apoptosis, we not only demonstrated first that Cdk5, p35, and p25 proteins were all expressed in prostate cancer cells (including lymph node carcinoma of the prostate (LNCaP) and DU-145 cells), but also showed where p25 formation and Cdk5 kinase activity were affected by treatment with digoxin. The inhibitor of p35 cleavage (calpeptin) was used to reduce p25 formation, and the result suggested that p25 accumulation might be the major cause of digoxin-triggered LNCaP cell death. Butyrolactone-I and roscovitine, two Cdk5 kinase inhibitors, were also found to prevent digoxin-triggered LNCaP cell death. In addition, treatment of siRNA-Cdk5 diminished digoxin-triggered cell death, as compared with the treatments of siRNA-Cdk1 or siRNA-Cdk2, which implies the specific involvement of Cdk5 in digoxin-triggered cell death. Caspase inhibitor set and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay were used to demonstrate that digoxin-triggered LNCaP cell apoptosis through Cdk5 activation. These results suggest that Cdk5/p35 and p25 are novel players in digoxin-triggered prostate cancer cell apoptosis and, therefore, become potential therapeutic targets.

Topics: 4-Butyrolactone; Apoptosis; Calcium; Caspase Inhibitors; Caspases; Cell Line, Tumor; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases; Digoxin; Dipeptides; Enzyme Activation; Enzyme Inhibitors; Humans; Male; Nerve Tissue Proteins; Prostatic Neoplasms; Purines; RNA, Small Interfering; Roscovitine

Digitalis or cardiac glycosides have been noted to induce tumor static or oncolytic effects in various types of cancer. We evaluated the effects and underlying mechanisms of cardiac glycosides, including digoxin, digitoxin and ouabain, on the proliferation of hormone dependent and independent prostate cancer cell lines.. Cell proliferation of the 3 human prostate cancer cell lines LNCaP, DU145 and PC3 was measured by 3-(4,5-dimethylthiazol-2-yle)2,5-diphenyltetralozium bromide (Sigma Chemical Co., St. Louis, Missouri) colorimetric assay. The cytotoxic effects of digitalis on prostate cancer cells were determined by lactate dehydrogenase measurements of the culture medium. Intracellular Ca2+ was measured by a dual wavelength spectrometer system. The percent of apoptotic cells after digitalis treatment was measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling and flow cytometry.. Digoxin, digitoxin and ouabain significantly inhibited the proliferation of LNCaP, DU145 and PC3 cells at a dose of 1 or 10 microM. after 1 to 4 days of culture. Cytotoxicity of digitalis on the DU145 and LNCaP cells was dose dependent but cytotoxicity was not obvious in PC3. Digitalis (1 microM.) significantly increased intracellular Ca2+ in LNCaP and DU145 after 12 hours of culture but PC3 cells needed a 24-hour treatment to show any effect. In the apoptosis measurement digitalis at a dose of 1 and 10 microM. also significantly increased the percent of apoptotic cells in the LNCaP, DU145 and PC3 cell lines. Normal control human glomerular epithelial cells showed no response to digitalis treatment at all tested doses.. Digitalis may inhibit the proliferation of prostate cancer cell lines, although the 3 cell lines showed varied sensitivity to digitalis. These effects are possibly the result of a mechanism involving sustained elevation of the concentration of intracellular Ca2+ and of apoptosis.

Topics: Apoptosis; Cell Division; Colorimetry; Digitalis Glycosides; Digitoxin; Digoxin; Enzyme Inhibitors; Humans; Male; Ouabain; Prostatic Neoplasms; Tumor Cells, Cultured

Cardiac glycosides are used clinically to increase contractile force in patients with cardiac disorders. Their mechanism of action is well established and involves inhibition of the plasma membrane Na+/K+-ATPase, leading to alterations in intracellular K+ and Ca(2+) levels. Here, we report that the cardiac glycosides oleandrin, ouabain, and digoxin induce apoptosis in androgen-independent human prostate cancer cell lines in vitro. Cell death was associated with early release of cytochrome c from mitochondria, followed by proteolytic processing of caspases 8 and 3. Oleandrin also promoted caspase activation, detected by cleavage poly(ADP-ribose) polymerase and hydrolysis of a peptide substrate (DEVD-pNA). Comparison of the rates of apoptosis in poorly metastatic PC3 M-Pro4 and highly metastatic PC3 M-LN4 subclones demonstrated that cell death was delayed in the latter because of a delay in mitochondrial cytochrome c release. Single-cell imaging of intracellular Ca(2+) fluxes demonstrated that the proapoptotic effects of the cardiac glycosides were linked to their abilities to induce sustained Ca(2+) increases in the cells. Our results define a novel activity for cardiac glycosides that could prove relevant to the treatment of metastatic prostate cancer.

Topics: Adenocarcinoma; Apoptosis; Calcium; Cardenolides; Cardiac Glycosides; Cardiotonic Agents; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Separation; Cytochrome c Group; Digoxin; DNA Fragmentation; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Male; Myocardium; Ouabain; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; Time Factors; Tumor Cells, Cultured

Topics: Adenocarcinoma; Aged; Atrial Fibrillation; Blood Transfusion; Cephalothin; Digoxin; Disseminated Intravascular Coagulation; Gangrene; Gastrointestinal Hemorrhage; Gentamicins; Heparin; Humans; Hydronephrosis; Hypothermia; Lymphatic Metastasis; Male; Prostatic Neoplasms; Pyelonephritis; Stomach Neoplasms; Vitamin K

Topics: Adenocarcinoma; Aged; Blood Glucose; Carbutamide; Diabetes Mellitus; Diethylstilbestrol; Digoxin; Drug Interactions; Heart Diseases; Humans; Jaundice; Lipids; Liver Cirrhosis; Liver Function Tests; Male; Nitroglycerin; Prostatic Neoplasms; Triglycerides