digoxin and Breast-Neoplasms

Despite preclinical evidence supporting anti-cancer effects of cardiac glycosides, epidemiologic studies consistently show elevated breast cancer risk in digoxin users. We studied this association in the Nurses' Health Study cohort to evaluate influences of screening mammography and lifestyle-related risk factors. We followed 90,202 postmenopausal women from 1994 to 2010. Self-reported breast cancers were confirmed by medical record review. We fit Cox regression models to estimate associations between time-varying digoxin use and breast cancer incidence, overall and by tumor ER status, accounting for mammography screening and established breast cancer risk factors. There were 5,004 digoxin users over 1.05 million person-years of observation, among whom 144 breast cancer cases occurred. Digoxin users were more likely to undergo mammographic screening, to be former users of postmenopausal hormones, and to take other medications than never-users; the groups were similar on reproductive history and alcohol consumption. Current digoxin use of >4-year duration was associated with a 45 % increased rate of breast cancer compared with never use (HRadj = 1.45, 95 % CI 1.13-1.86). The association appeared stronger for ER-positive disease (HRadj = 1.46, 95 % CI 1.10-1.95) than for ER-negative disease (HRadj = 1.12, 95 % CI 0.52-2.37). Associations were robust to restriction on regular mammography use and to adjustment for established breast cancer risk factors, including lifestyle-related exposures. The positive association between digoxin use and breast cancer occurrence was not attenuated when lifestyle-related breast cancer risk factors and screening practices were accounted for. Digoxin, a common cardiac drug worldwide, may promote breast carcinogenesis.

Topics: Aged; Breast Neoplasms; Digoxin; Early Detection of Cancer; Female; Humans; Incidence; Longitudinal Studies; Mammography; Mass Screening; Middle Aged; Postmenopause; Proportional Hazards Models; Reproductive History; Risk; Risk Factors; United States

Digoxin, a phyto-estrogen, binds with estrogen receptors (ER) and can cause gynecomastia. Among women currently using digoxin, breast and uterus cancer incidences are significantly increased (approximate risk ratios, 1.3-1.5). Both cancers are often estrogen sensitive. In contrast, ovary and cervix cancers are relatively estrogen insensitive, and incidence is unaffected by digoxin exposure. When digoxin use stops, incidence rapidly reverts to that in nonusers. These patterns parallel those of estrogen, suggesting that digoxin works via ER-stimulated proliferation of ductal and/or acinar cells, accelerating the growth of nascent cancers. Also consistent with an estrogenic effect, men using digoxin have a small but significant reduction in prostate cancer (risk ratio, 0.76). Other estrogen-like drugs, particularly spironolactone, should be investigated for similar effects. The effect of digoxin use in women being treated for breast cancer or in survivors is unknown. Women with estrogen-sensitive cancers on adjuvant therapy may take tamoxifen, which blocks ERs. However, postmenopausal patients may use aromatase inhibitors, which block estrogen production while leaving ERs susceptible to digoxin. If adverse effects are found, tamoxifen may be preferred over aromatase inhibitors in patients receiving estrogen-mimicking drugs. Alternatively, other cardiotropic drugs might be considered in women with or at high risk of developing estrogen-sensitive cancers.

Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Digoxin; Estrogens; Female; Humans; Male; Neoplasms, Hormone-Dependent; Phytoestrogens; Receptors, Estrogen; Risk Factors; Selective Estrogen Receptor Modulators; Spironolactone; Tamoxifen; Uterine Neoplasms

Many medications have been developed for one purpose but then are found to have other clinical activities. There is tremendous interest in whether non-cancer medications may potentially have effects on breast cancer survival. In this review article, we have presented and evaluated the evidence for several commonly used over-the-counter and prescription medications - including aspirin (and other non-steroidal anti-inflammatory drugs), beta-blockers, angiotensin-converting enzyme inhibitors, statins, digoxin, and metformin - that have been evaluated among breast cancer survivors in prospective studies. Substantial scientific evidence supports the hypothesis that some of these common and relatively safe drugs may reduce breast cancer mortality among those with the disease by an amount that rivals the mortality reduction gained by currently used therapies. In particular, the evidence is strongest for aspirin (approximately 50% reduction), statins (approximately 25% reduction), and metformin (approximately 50% reduction). As these drugs are generic and inexpensive, there is little incentive for the pharmaceutical industry to fund the randomized trials that would show their effectiveness definitively. We advocate that confirmation of these findings in randomized trials be considered a high research priority, as the potential impact on human lives saved could be immense.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Breast Neoplasms; Digoxin; Drug Repositioning; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metformin; Off-Label Use

The potential for an interaction between lapatinib and absorption of the P-glycoprotein (ABCB1) substrate digoxin at a therapeutic dose in breast cancer patients was characterized. Seventeen women with HER2-positive metastatic breast cancer received a single oral 0.5-mg dose of digoxin on days 1 and 9 and oral lapatinib 1500 mg once daily on days 2 through 9. Digoxin pharmacokinetic parameters were determined on day 1 (digoxin administration alone) and on day 9 (coadministration of lapatinib and digoxin), and parameters were compared to determine the effects of lapatinib on digoxin absorption. Concomitant medications that could affect ABCB1 were accounted for. Lapatinib 1500 mg/day increased digoxin absorption approximately 80%, implicating lapatinib inhibition of intestinal ABCB1-mediated efflux. In summary, coadministration of lapatinib with narrow therapeutic index drugs that are substrates of ABCB1 should be undertaken with caution and dose adjustment should be considered.

Topics: Administration, Oral; Adult; Alberta; Antineoplastic Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; Breast Neoplasms; Cardiotonic Agents; Cross-Over Studies; Digoxin; Drug Interactions; Female; Gastrointestinal Absorption; Half-Life; Humans; Lapatinib; Metabolic Clearance Rate; Middle Aged; Protein Kinase Inhibitors; Quinazolines; Risk Assessment; Seoul

As a first-in-class, selective, potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation. An in vitro study showed that enasidenib at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-glycoprotein, breast cancer resistance protein, organic anion transporter (OAT) P1B1, and OATP1B3 transporters. Therefore, a drug-drug interaction study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics of several probe compounds in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome, including the probes herein described in this article, digoxin and rosuvastatin. Results from 8 patients (all Asian) with a mean age of 67.1 years showed that following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), digoxin's (0.25 mg) area under the plasma concentration-time curve from time 0 to 30 days was 1.2-fold (90% confidence interval, 0.9-1.6), compared with digoxin alone. Following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), rosuvastatin's (10 mg) area under the plasma concentration-time curve from time 0 to infinity was 3.4-fold (90% confidence interval, 2.6-4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs that are substrates of P-glycoprotein, breast cancer resistance protein, OATP1B1, and OATP1B3 transporters, when used concomitantly with enasidenib.

Topics: Aged; Aminopyridines; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Breast Neoplasms; Digoxin; Drug Interactions; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Membrane Transport Proteins; Myelodysplastic Syndromes; Neoplasm Proteins; Pharmaceutical Preparations; Recurrence; Rosuvastatin Calcium; Triazines

Anthracyclines have cardiotoxic side effects. Cardioprotective drugs such as angiotensin-converting enzyme inhibitors and beta-blockers are therefore recommended for patients with anthracycline-induced cardiomyopathy. We herein present a 54-year-old woman with recurrent metastatic breast cancer who developed heart failure (HF) with a left ventricular ejection fraction (LVEF) of 22% after undergoing epirubicin chemotherapy. However, her HF symptoms and low LVEF persisted despite 5 months of cardioprotective therapy and additional oral pimobendan. Pimobendan was discontinued because of ventricular arrhythmia and hypotension. After the start of low-dose (0.125 mg daily) digoxin, her LVEF increased to 42%, and her HF symptoms improved with no adverse events.

Topics: Anthracyclines; Breast Neoplasms; Cardiomyopathies; Digoxin; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Stroke Volume; Ventricular Function, Left

Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.

Topics: A549 Cells; Animals; Antibiotics, Antineoplastic; Apoptosis; Bleomycin; Breast Neoplasms; Cardiac Glycosides; Cell Line, Tumor; Cell Membrane; Cellular Senescence; Chondrocytes; Digoxin; Female; Fibroblasts; Humans; Hydrogen-Ion Concentration; Mice; Osteoarthritis; Ouabain; Proscillaridin; Pulmonary Fibrosis; Xenograft Model Antitumor Assays

Myriad reports suggest that frequently used prescription drugs alter the viability of breast cancer cells in pre-clinical studies. Routine use of these drugs, therefore, may impact breast cancer prognosis, and could have important implications for public health.. The Danish Breast Cancer Group (DBCG) clinical database provides high-quality prospectively collected data on breast cancer diagnosis, treatment, and routine follow-up for breast cancer recurrence. Individual-level linkage of DBCG data to other population-based and medical registries in Denmark, including the Danish National Prescription Registry, has facilitated large population-based pharmacoepidemiology studies. A unique advantage of using DBCG data for such studies is the ability to investigate the association of drugs with breast cancer recurrence rather than breast cancer mortality - which may be misclassified - or all-cause mortality. Here we summarize findings from pharmacoepidemiological studies, based on DBCG data, on the association between routinely used prescription drugs and risk of breast cancer recurrence.. Our findings suggest that concurrent use of glucocorticoids, ACE inhibitors, aspirin, NSAIDs, selective COX-2 inhibitors, digoxin, and opioids has little impact on breast cancer recurrence. Similarly, patients who use SSRIs concurrently with tamoxifen treatment are not at increased risk of recurrence. In contrast, post-diagnostic use of simvastatin, a lipophilic statin, correlates with a decreased risk of breast cancer recurrence, providing a rationale for a prospective randomized clinical trial investigating simvastatin as an adjuvant therapy for breast cancer.. As a whole, findings of pharmacoepidemiological studies based on DBCG data provide reassurance to physicians and healthcare personnel who provide supportive care during and after cancer (including prescriptions for comedications) and to breast cancer survivors for whom the risk of breast cancer recurrence is a major concern.

Topics: Adrenergic beta-Antagonists; Analgesics, Opioid; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Breast Neoplasms; Cardiotonic Agents; Cyclooxygenase 2 Inhibitors; Databases, Factual; Denmark; Digoxin; Disease Progression; Estrogen Antagonists; Female; Glucocorticoids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neoplasm Recurrence, Local; Platelet Aggregation Inhibitors; Prognosis; Selective Serotonin Reuptake Inhibitors; Simvastatin; Tamoxifen

Digoxin is a kind of plant-derived cardiac glycoside that is mainly used to treat heart diseases, especially in congestive heart failure or arrhythmia. However, its potentiality presented in anti-tumor remains unexplored. The purpose of this study was designed to investigate the beneficial pharmacological activity of digoxin on breast cancer cell line (MDA-MB-231, MM231).. The methyl thiazolyl tetrazolium (MTT) assay was utilized to detect the proliferation of the breast cancer MM231. The apoptotic cell numbers were determined by the flow cytometry analysis. The expressions of Bcl-2 (B-cell lymphoma-2) and Bax (Bcl2-associated X protein) were detected by Western blot analysis.. Digoxin dose-dependently blocked the cell growth of the breast cancer MM231 through MTT assay, whereas the apoptotic numbers were significantly elevated as reflected in acridine orange staining and flow cytometry analysis. In addition, findings from Western blotting method indicated that digoxin intervention showed reduced Bcl-2 expression and elevated Bax level in MM231 cells, characterized by increased Bax/Bcl-2 ratio.. Digoxin plays a potential anti-tumor role in breast cancer in vitro, possibly by inducing mitochondria-dependent apoptosis.

Topics: Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Digoxin; Female; Humans; Proto-Oncogene Proteins c-bcl-2

Using the model of breast cancer Ehrlich ascites tumor in mice, we showed that a sigle intraperitoneal injection of cardiac glycoside digoxin 1 h before the intraperitoneal injection of cisplatin increased the anticancer effect of the cytostatic drug more than twice when recalculated for the dose. It is assumed that the modifying effect of digoxin is determined by the direct inhibition of glycolysis in tumor cells. Taking into account the design of the study, we consider promising the clinical evaluation of the effectiveness of digoxin as a modifier of cisplatin efficiency in intracavitary therapy of ascites cancers with pleural and abdominal dissenmination.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Ehrlich Tumor; Cisplatin; Digoxin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glycolysis; Mice, Inbred CBA; Neoplasm Transplantation; Treatment Outcome

Digoxin has been shown to have an estrogenic effect and is associated with increased risk of gynecomastia and estrogen-sensitive cancers such as breast and uterus cancer. These findings, particularly recent observations of increased breast cancer risk, raise questions about the safety of digoxin use in breast cancer patients. Therefore, we investigated whether digoxin use after breast cancer diagnosis increased the risk of breast cancer-specific mortality in breast cancer patients. A cohort of 17,842 breast cancer patients newly diagnosed from 1998 to 2009 was identified from English cancer registries (from the National Cancer Data Repository). This cohort was 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 breast 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 breast cancer-specific and all-cause mortality. In 17,842 breast cancer patients, there were 2219 breast cancer-specific deaths. Digoxin users appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.73; 95 % CI 1.39-2.15) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.91; 95 % CI 0.72-1.14). In this large population-based breast cancer cohort study, there was little evidence of an increase in breast cancer-specific mortality with digoxin use after diagnosis. These results provide some reassurance that digoxin use is safe in breast cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Cause of Death; Cohort Studies; Comorbidity; Digoxin; England; Female; Humans; Middle Aged; Mortality; Neoplasm Grading; Neoplasm Staging; Population Surveillance; Registries; Risk Factors

Topics: Breast Neoplasms; Cardiotonic Agents; Cardiovascular Diseases; Digoxin; Female; Humans; Risk Factors

The aim of this study was to investigate the effects of digoxin on the chemoresistance of human breast cancer cell line MCF-7/adriamycin (ADR) and its underlying mechanism. MCF-7 and MCF-7/ADR cells were designated as control and ADR groups, respectively. MCF-7/ADR cells in ADR + digoxin group received 48 h of digoxin (10 nmol/L) treatment; MCF-7/ADR cells transfected with pLKO.1-shHIF-1α and pLKO.1-shcontrol plasmids were named shHIF-1α and shcontrol groups, respectively. CCK-8 assay was employed to detect the cytotoxic effect of ADR on MCF-7/ADR cells, and IC50 value and resistance index were calculated according to CCK-8. RT-PCR was used to measure the mRNA levels of hypoxia inducible factor-1α (HIF-1α) and multidrug resistance-1 (MDR1). Western blot was used to analyze the protein levels of HIF-1α and MDR1. Flow cytometry was used to determine the apoptosis. The result showed that the resistance index of MCF-7/ADR cells was 115.6, and it was reduced to 47.2 under the action of digoxin (P < 0.05). In comparison with control group, ADR groups showed increased protein and mRNA levels of HIF-1α and MDR1 (P < 0.05). Digoxin reduced the protein levels of HIF-1α and MDR1, as well as the mRNA level of MDR1, but did not affect the mRNA level of HIF-1α. After HIF-1α gene was silenced, the protein levels of HIF-1α and MDR1 were down-regulated (P < 0.05), and the pro-apoptotic effect of ADR on MCF-7/ADR cells was enhanced. Although it was also observed that digoxin promoted cell apoptosis in both shcontrol and shHIF-1α groups, the difference between the two groups was not significant. In conclusion, the results suggest that digoxin may partially reverse the ADR resistance in human breast cancer cell line MCF-7/ADR by means of down-regulating the expression levels of HIF-1α and MDR1 and promoting apoptosis via HIF-1α-independent pathway.

Topics: Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Breast Neoplasms; Digoxin; Doxorubicin; Drug Resistance, Neoplasm; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; MCF-7 Cells; RNA, Messenger; Transfection

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

Digoxin use is associated with increased incidence of breast and uterus cancers. We postulated that digoxin use might affect tumor characteristics and increase relapse risk in women with breast cancer.. Incident breast cancer cases in Danish women (n = 49,312; 1995 to 2008) were identified. Analyses were conducted in women 20 to 74 years old. Relapse hazard ratios (HR) were compared in women using and not using digoxin, adjusting for age, calendar period, protocol, tumor size, nodal involvement, histology grade, estrogen-receptor (ER) status, and anti-estrogen therapy in Cox regression models.. At diagnosis, tumors in digoxin users were more likely ER+ (85.4% vs. 78.6%: P = 0.002) and have grade 1 ductal histology (37.2% vs. 25.7%; P = 0.004), compared to non-users. 45 relapses occurred in women already using digoxin at breast cancer diagnosis (1,487 person-years); 24 relapses occurred in women later starting digoxin (384 person-years). Overall relapse risk HR in digoxin users was 1.13 (95% confidence interval: 0.88, 1.46) compared to non-users. Relapse risk in digoxin users was significantly increased in the first year (2.19; 1.26, 3.78) but not thereafter (0.99; 0.74, 1.32) (P = 0.02 for difference in HRs). First-year relapse hazard was high in digoxin-using women with ER+ tumors (2.51; 1.39, 4.55) but not ER- tumors (0.72; 0.10, 5.27). Recurrence hazard was not significantly changed among digoxin-using women also using tamoxifen.. Breast cancers arising in digoxin-using women had better prognostic features. After adjustment for markers, overall breast cancer relapse risk in digoxin users was not increased significantly, although recurrence hazards for ER+ tumors were higher in the first year following diagnosis.

Topics: Adult; Aged; Aromatase Inhibitors; Breast Neoplasms; Denmark; Digoxin; Female; Heart Diseases; Humans; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Receptors, Estrogen; Risk Factors; Tamoxifen

Several epidemiological studies, some of which included several thousand women, have shown a link between digoxin exposure and the risk of breast cancer. A cohort study of women with angina, identified in the Danish Prescription Registry, showed a statistically significant increase in the risk of breast cancer among women taking digoxin compared with those not taking digoxin. An increase in the risk of breast cancer of similar magnitude was observed in a case-control study based on Danish hospital registries. In both studies, the risk of breast cancer was increased by about one-third with digoxin (relative risk around 1.3). A causal link is plausible, given the oestrogen-like properties of digoxin. In practice, this risk must be taken into account, especially in patients at risk of breast cancer. Women should be informed of the increased risk of breast cancer before deciding whether the impact of digoxin on cardiac symptoms warrants taking this risk.

Topics: Breast Neoplasms; Cardiotonic Agents; Denmark; Digoxin; Female; Humans; Risk

Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through increased expression of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins, enzymes that remodel collagen at the metastatic site and recruit bone marrow-derived cells (BMDCs) to the metastatic niche. We investigated the effect of two chemically and mechanistically distinct HIF inhibitors, digoxin and acriflavine, on breast cancer metastatic niche formation. Both drugs blocked the hypoxia-induced expression of LOX and LOXL proteins, collagen cross-linking, CD11b⁺ BMDC recruitment, and lung metastasis in an orthotopic breast cancer model. Patients with HIF-1 α-overexpressing breast cancers are at increased risk of metastasis and mortality and our results suggest that such patients may benefit from aggressive therapy that includes a HIF inhibitor.

Topics: Acriflavine; Amino Acid Oxidoreductases; Animals; Bone Marrow Cells; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Digoxin; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1; Lung Neoplasms; Mice; Mice, SCID; Neoplasm Metastasis; Protein-Lysine 6-Oxidase; Xenograft Model Antitumor Assays

Lymphatic dissemination from the primary tumor is a major mechanism by which breast cancer cells access the systemic circulation, resulting in distant metastasis and mortality. Numerous studies link activation of hypoxia-inducible factor 1 (HIF-1) with tumor angiogenesis, metastasis, and patient mortality. However, the role of HIF-1 in lymphatic dissemination is poorly understood. In this study, we show that HIF-1 promotes lymphatic metastasis of breast cancer by direct transactivation of the gene encoding platelet-derived growth factor B (PDGF-B), which has proliferative and chemotactic effects on lymphatic endothelial cells. Lymphangiogenesis and lymphatic metastasis in mice bearing human breast cancer orthografts were blocked by administration of the HIF-1 inhibitor digoxin or the tyrosine kinase inhibitor imatinib. Immunohistochemical analysis of human breast cancer biopsies demonstrated colocalization of HIF-1α and PDGF-B, which were correlated with lymphatic vessel area and histological grade. Taken together, these data provide experimental support for breast cancer clinical trials targeting HIF-1 and PDGF-B.

Topics: Benzamides; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Chromatin Immunoprecipitation; Digoxin; Female; Humans; Hypoxia-Inducible Factor 1; Imatinib Mesylate; Immunoblotting; Immunohistochemistry; Luciferases; Lymphangiogenesis; Lymphatic Metastasis; Piperazines; Proto-Oncogene Proteins c-sis; Pyrimidines; RNA, Small Interfering; Transcriptional Activation

Digoxin resembles estrogen chemically and may have estrogenic effect. We hypothesized that digoxin use might increase breast cancer incidence and examined if use might be associated with risk of breast cancer, categorized by estrogen receptor (ER) status. To determine if being under care for heart disease biased the findings, rate ratios in users of angina drugs were similarly evaluated as a control exposure group.. Women using digoxin and angina drugs were identified in the nationwide Danish Prescription Database, available between 1995 and 2008. Incident breast cancers were identified in the Danish Cancer Registry and further classifying by ER status. Relative risks (RR) were compared to nonusers using age- and period-adjusted incidence rate ratios.. Two thousand one hundred forty-four of 104,648 women using digoxin developed breast cancer. Current digoxin users were at increased risk of breast cancer (RR, 1.39; 95% CI, 1.32 to 1.46), but risk was not increased in former users (RR, 0.91; 95% CI, 0.83 to 1.00). The increased risks in digoxin users were marginally higher for ER-positive breast cancers (RR, 1.35; 95% CI, 1.26 to 1.45) and ER unknown breast cancers (RR, 1.51; 95% CI, 1.38 to 1.64) than for ER-negative breast cancers (RR, 1.20; 95% CI, 1.03 to 1.40). Among 137,493 women exposed to angina drugs only (a comparison group with cardiovascular disease; n = 2,658 breast cancers), incidence was not increased in current or former users.. Women currently using digoxin had a significantly increased risk of breast cancer. Risk normalized when digoxin was stopped. No risk increases were observed in women using angina drugs only. The higher risk of developing ER-positive breast cancers supports an estrogen-mimicking mechanism.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Breast Neoplasms; Cardiotonic Agents; Digoxin; Female; Humans; Incidence; Middle Aged; Receptors, Estrogen; Risk Factors; Young Adult

Topics: Angiogenesis Inhibitors; Animals; Anthracyclines; Antibiotics, Antineoplastic; Breast Neoplasms; Cell Hypoxia; Digoxin; Female; Humans; Hypoxia-Inducible Factor 1; Lung Neoplasms; Male; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Transplantation, Heterologous

Laboratory and epidemiologic studies have suggested a modifying effect of cardiac glycosides (for example, digoxin and digitoxin) on cancer risk. We explored the association between digoxin treatment and invasive breast cancer incidence among postmenopausal Danish women.. We used Danish registries to identify 5,565 postmenopausal women diagnosed with incident invasive breast carcinoma between 1 January 1991 and 31 December 2007, and 55,650 matched population controls. Cardiac glycoside prescriptions were ascertained from county prescription registries. All subjects had at least 2 years of recorded prescription drug and medical history data. We estimated the odds ratio associating digoxin use with breast cancer in conditional logistic regression models adjusted for age, county of residence, and use of anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, and hormone replacement therapy. We also explored the impact of confounding by indication and detection bias.. Digoxin was the sole cardiac glycoside prescribed to subjects during the study period. There were 324 breast cancer cases (5.8%) and 2,546 controls (4.6%) with a history of digoxin use at least 1 year before their index date (adjusted odds ratio (OR): 1.30; 95% confidence interval: 1.14 to 1.48). The breast cancer OR increased modestly with increasing duration of digoxin exposure (adjusted OR for 7 to 18 years of digoxin use: 1.39; 95% confidence interval: 1.10 to 1.74). The association was robust to adjustment for age, receipt of hormone replacement therapy, coprescribed drugs, and confounding by indication. A comparison of screening mammography rates between cases and controls showed no evidence of detection bias.. Our results suggest that digoxin treatment increases the risk of invasive breast cancer among postmenopausal women.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Cardiotonic Agents; Cardiovascular Diseases; Case-Control Studies; Digitoxin; Digoxin; Female; Humans; Incidence; Middle Aged; Postmenopause; Prospective Studies; Risk Factors

We examined the effects of three cardiac glycosides, ouabain, digoxin and proscillaridin A, on the proliferation of estrogen independent MDA-MB-231 breast cancer cells. In terms of reduction in cell viability, the compounds rank for both 24 h and 48 h of incubation in MDA-MB-231 cells in the order proscillaridin A > digoxin > ouabain. Digoxin for 24 h and 48 h of incubation in MDA-MB-231 cells proved to be only slightly more potent than ouabain, with IC50 values of 122 +/- 2 and 70 +/- 2 nM, respectively, compared to 150 +/- 2 and 90 +/- 2 nM for ouabain. In contrast, proscillaridin A, was much more active and showed a high level of cytotoxic potency, IC50 51 +/- 2 and 15 +/- 2 nM for 24 h and 48 h of incubation, respectively. The concentrations of digoxin, ouabain and proscillaridin A needed to inhibit [3H]thymidine incorporation into DNA by 50% (IC50) in MDA-MB-231 cells for 24 h of incubation were found to be 124 +/- 2 nM, 142 +/- 2 nM, and 48 +/- 2 nM, respectively. In the present study, we demonstrated that ouabain, digoxin, and proscillaridin A induce apoptosis in MDA-MB-231 cells by increasing free calcium concentration and by activating caspase-3.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Calcium; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Digoxin; Dose-Response Relationship, Drug; Enzyme Activation; Female; Humans; Inhibitory Concentration 50; Ouabain; Proscillaridin; Time Factors

We evaluated the cytotoxicity and underlying mechanisms of cardiac glycosides, including digoxin, ouabain and proscillaridin A, on the proliferation of breast cancer MCF-7 cells. In terms of inhibition of cell proliferation of MCF-7 cells, the compounds rank in the order proscillaridin A>digoxin>ouabain. While both digoxin and ouabain inhibited topoisomerase II catalytic activity at nanomolar concentrations (100 nM), neither agent inhibited topoisomerase I catalytic activity even at concentrations as high as 100 microM. On the other hand, proscillaridin A was a potent poison of topoisomerase I and II activity at nanomolar drug concentrations (30 nM, 100 nM, respectively), suggesting that this agent may produce its cytotoxic activity by targeting both enzymes simultaneously. These studies suggest that the stabilization of DNA-topoisomerase II complexes is closely linked to the mechanism of digoxin, ouabain and proscillaridin A cytotoxicity. The potential DNA-binding properties of the cardiac glycosides have been assessed by measuring the displacement of ethidium bromide from calf thymus DNA. These results indicate that digoxin, ouabain and proscillaridin A neither intercalate nor interact with the minor groove of DNA.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Survival; Digoxin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Kinetics; Models, Molecular; Ouabain; Proscillaridin; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors

P-glycoprotein, encoded by the MDR-1 gene, confers multi-drug resistance against antineoplastic agents and is important for the transmembrane transition of various other common therapeutic drugs. Recently, a number of polymorphisms in the MDR-1 gene were identified and the T/T genotype at position 3435 in exon 26 was found to correlate with intestinal P-glycoprotein expression and bioavailability of digoxin after oral administration. We analysed the allelic frequencies at the polymorphic site C3435T in a group of patients with locally advanced breast cancer treated by preoperative chemotherapy to evaluate its predictive value. Sixty-eight patients diagnosed between 1998 and 2001 were treated by preoperative chemotherapy with anthracyclines or these agents combined with taxanes. From genomic DNA, a 106 bp fragment of MDR-1 exon 26 was amplified and the C3435T genotype was determined by Pyrosequencing methodology. A potential correlation with therapeutic response was calculated with Fisher's exact test. The overall clinical response rate (cCR and cPR) was 68% but only 7 patients (10.3%) achieved pathological complete response (pCR). Heterozygous C3435T occurred in 57% of the subjects and 22% of the analysed individuals possessed only T alleles. Statistical analysis revealed a significant correlation (p=0.029) between clinical complete response to preoperative chemotherapy and the T/T genotype. MDR-1 polymorphism C3435T in exon 26 may co-determine resistance to chemotherapy and provide useful information to individualize therapy.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Breast Neoplasms; Chemotherapy, Adjuvant; Digoxin; Exons; Female; Genes, MDR; Genotype; Humans; Lymphatic Metastasis; Menopause; Middle Aged; Polymorphism, Single Nucleotide; Predictive Value of Tests; Receptors, Estrogen; Receptors, Progesterone; Treatment Outcome; Tumor Suppressor Protein p53

We experienced sudden cardiac arrest after induction of general anesthesia using isoflurane. The patient had had paroxysmal atrial fibrillation for one year and had been treated with digoxin and cibenzoline succinate. Sinus rhythm appeared soon after the start of closed chest compression. However cardiac arrest recurred, and we inserted a temporary pacemaker catheter to stabilize the circulatory status. She awoke from anesthesia without any complications. The diagnosis of sick sinus syndrome (SSS) was made postoperatively and she had a permanent pacemaker implanted. We thought that the hidden SSS had been the cause of this sudden cardiac arrest.

Topics: Aged; Anesthesia, General; Anesthetics, Inhalation; Anti-Arrhythmia Agents; Atrial Fibrillation; Breast Neoplasms; Digoxin; Female; Heart Arrest; Humans; Imidazoles; Isoflurane; Mastectomy; Pacemaker, Artificial; Sick Sinus Syndrome

Topics: Breast Neoplasms; Cardiotonic Agents; Digoxin; Diuretics; Drug Interactions; Female; Heart Failure; Humans; Hypertension; Middle Aged; Tamoxifen

Topics: Breast Neoplasms; Cardiac Glycosides; Cell Division; Digitalis; Digitoxin; Digoxin; Female; Humans; Plants, Medicinal; Plants, Toxic; Tumor Cells, Cultured

Four evaluations of ambulatory medical care tasks were developed for use in quality assurance. The evaluations used medical records data and explicit criteria incorporating branching logic. They were implemented in eight general medicine provider groups in two teaching hospitals and six related health centers. Agreement with criteria among 316 provider responses to questionnaires varied from 57% to 100%. The percentage of cases with one or more variation from evaluation criteria, confirmed on peer review to have a deficiency in care, ranged by task from 6% to 42%, with substantial variation between sites. Physician reviewers from each site varied in leniency. Numbers of actions taken to correct deficiencies ranged by site and task from zero to six. Multisite evaluations revealed differences in performance and efforts to improve that are not apparent when each site conducts its own evaluations. More uniformly effective and impartial quality assurance is needed to correct some important deficiencies in care observed in this study.

Topics: Adult; Ambulatory Care; Blood Glucose; Breast Neoplasms; Digoxin; Evaluation Studies as Topic; Female; Follow-Up Studies; Group Practice; Hematocrit; Humans; Peer Review; Quality Assurance, Health Care; United States; Uterine Cervical Neoplasms

10 biopsy specimens of primary breast tumours from 10 patients were classified histopathologically into 8 ductal carcinomas and 2 lobular carcinomas. Portions of tumour of approximately 1 mm3 were cultured in Medium 199 buffered with 20 mM Hepes for 48 h with or without addition of digoxin at concentrations from 1-2 ng/ml to 10-20 micrograms/ml of culture medium. Measurement of DNA synthesis by [3H]-thymidine incorporation, DNA analysis and histological examination showed that 5 biopsy specimens demonstrated epithelial cell survival in culture. These cultures were significantly (p less than 0.001) affected by digoxin at concentrations above 10-20 ng/ml, with suppression of [3H]-thymidine incorporation and reduced epithelial cell viability. Parallel studies on 5 biopsy specimens of DMBA-induced rat mammary carcinomas showed no effects of digoxin up to 10 micrograms/ml of culture medium. These studies indicate the possibility of this class of drug being of use in growth suppression of breast tumours.

Topics: Animals; Breast Neoplasms; Carcinoma; Carcinoma, Intraductal, Noninfiltrating; Cell Survival; Digoxin; DNA, Neoplasm; Dose-Response Relationship, Drug; Female; Humans; Organ Culture Techniques; Rats; Rats, Inbred Strains

Topics: Breast Neoplasms; Cell Nucleus; Digoxin; Female; Humans; Neoplasm Staging

Topics: Breast Neoplasms; Cytosol; Digoxin; Estradiol; Female; Humans; Receptors, Estrogen; Receptors, Progesterone