Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications

Abstract

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.

Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission

“…Piceatannol has been reported to act as a receptor antagonist in breast cancer cells, via its estrogen-like activity (57). However, the mode of action of piceatannol is likely to be different in ovarian cancer cell lines because breast cancers (and uterine cancers) are often estrogen-sensitive, whereas ovarian and cervical cancers are relatively estrogen-insensitive (58). The Drp1-dependent increases in mitochondrial fission observed point to the possible involvement of its regulator, the calcium-dependent phosphatase calcineurin.…”

Digoxin Use After Diagnosis of Colorectal Cancer and Survival: A Population-Based Cohort Study

“…For instance, studies have shown increases in breast and uterus cancer probably related to estrogenic effects of digoxin (1). A recent large UK study reported a 40% increase in colorectal cancer risk in digoxin users (2), which the researchers suggest possibly reflects direct effects of the sodium potassium ATPase pump on tumorigenic pathways such as the Src/MAPK (3).…”

Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

“…Digoxin is a phyto-estrogen [1] used to treat heart failure and supra-ventricular arrhythmias (atrial fibrillation/flutter) [2]. Early animal studies indicate that digoxin may bind to estrogen receptors (ER) [1] and have estrogenic effects.…”

“…Early animal studies indicate that digoxin may bind to estrogen receptors (ER) [1] and have estrogenic effects. In support of this digoxin is a recognized cause of gynecomastia [3], and digoxin use has been associated with increased risk of estrogen-sensitive cancers such as uterus cancer [4].…”

“…Randomized controlled trials [5] and observational studies [6] have shown that exogenous estrogens can increase breast cancer risk, thus suggesting that the potential estrogenic effect of digoxin could influence breast cancer risk [1,[7][8][9]. Consequently, a number of epidemiological studies have shown increases in breast cancer risk in digoxin users.…”