Cardiac glycosides use and the risk and mortality of cancer; systematic review and meta-analysis of observational studies

Abstract

BackgroundCardiac glycosides (CGs) including digitalis, digoxin and digitoxin are used in the treatment of congestive heart failure and atrial fibrillation.Pre-clinical studies have investigated the anti-neoplastic properties of CGs since 1960s. Epidemiological studies concerning the association between CGs use and cancer risk yielded inconsistent results. We have performed a systematic review and meta-analysis to summarize the effects of CGs on cancer risk and mortality.MethodsPubMed, Scopus, Cochrane library, Medline and Web of Knowledge were searched for identifying relevant studies. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects model.ResultsWe included 14 case-control studies and 15 cohort studies published between 1976 and 2016 including 13 cancer types. Twenty-four studies reported the association between CGs and cancer risk and six reported the association between CGs and mortality of cancer patients.Using CGs was associated with a higher risk of breast cancer (RR = 1.330, 95% CI: 1.247–1.419). Subgroup analysis showed that using CGs increased the risk of ER+ve breast cancer but not ER-ve. Using CGs wasn’t associated with prostate cancer risk (RR = 1.015, 95% CI: 0.868–1.87). However, CGs decreased the risk in long term users and showed a protective role in decreasing the risk of advanced stages. CGs use was associated with increased all-cause mortality (HR = 1.35, 95% CI: 1.248–1.46) but not cancer-specific mortality (HR = 1.075, 95% CI: 0.968–1.194).ConclusionThe anti-tumor activity of CGs observed in pre-clinical studies requires high concentrations which can’t be normally tolerated in humans. However, the estrogen-like activity of CGs could be responsible for increasing the risk of certain types of tumors.

Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells

“…In other words, efficacious concentrations cannot be obtained in the tumor without considerable toxicity in the patient. Due to the structural similarity to estrogen, several studies have suggested that digoxin may actually increase the risk for estrogen receptor positive breast cancer [62,63]. Based on these findings, we hypothesized that digoxin may be a good candidate at lower doses in combinatorial therapies for TNBC patients.…”

Digoxin treatment reactivates in vivo radioactive iodide uptake and correlates with favorable clinical outcome in non‐medullary thyroid cancer

“…Some studies indicate that digoxin use is not significantly associated with cancer incidence or cancer-specific mortality in a number of malignancies [ 18 – 21 ]. In contrast, other human studies suggest that digoxin could modify cancer initiation or progression in certain tissue types [ 22 – 24 ]. Potential effects of digoxin treatment on NMTC development, progression and treatment response have not been studied so far.…”

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity

“…Moreover, also promising is the fact that a lower incidence in some types of cancer in patients on CG therapy (cardiac conditions) has been reported [ 4 ]. While another study claims the opposite [ 5 ], others stand somewhere in between [ 6 , 7 ]. However, what is quite certain and makes CGs a new hope for cancer treatment are clinical data showing that CGs, mainly digoxin, significantly prolong the survival of cancer patients otherwise treated with traditional chemotherapeutics.…”