Cardiac Glycosides and Breast Cancer

Stenkvist, Björn; Bengtsson, Eva; Eriksson, Olle; Holmquist, Jan; Nordin, Bo; Westman-Naeser, Sighild; Eklund, Gunnar

doi:10.1016/s0140-6736(79)90996-6

Cited by 134 publications

(90 citation statements)

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“…Five years after mastectomy, patients receiving cardiac glycosides had a f10-fold lower rate of relapse and improved survival, than patient not receiving these drugs (43)(44)(45)(46). Despite these clinical findings, the mechanism(s) by which cardiac glycosides exert an anticancer effect and prevent metastasis are unclear.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation

Simpson

Mawji²,

Anyiwe³

et al. 2009

Cancer Research

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Normal epithelial cells undergo apoptosis upon detachment from the extracellular matrix, a process termed ''anoikis.'' However, malignant epithelial cells with metastatic potential resist anoikis and can survive in an anchorage-independent fashion. Molecules that sensitize resistant cells to anoikis will be useful chemical probes to understand this pathway. To identify novel anoikis sensitizers in anoikis-resistant PPC-1 prostate adenocarcinoma cells, a library of 2,000 off-patent drugs and natural products was screened for their ability to preferentially induce cell death in suspension over adherent culture conditions. This screen identified five members of the family of cardiac glycosides as anoikis sensitizers, including ouabain, peruvoside, digoxin, digitoxin, and strophanthidin. We conducted further studies with ouabain to discern the mechanism of cardiac glycoside-induced anoikis sensitization. Ouabain initiated anoikis through the mitochondrial pathway of caspase activation. In addition, ouabain sensitized cells to anoikis by inhibiting its known target, the Na + /K + ATPase pump, and inducing hypoosmotic stress. Resistance to anoikis permits cancer cells to survive in the circulation and facilitates their metastasis to distant organs, so we tested the effects of Na + /K + ATPase inhibition on distant tumor formation in mouse models. In these mouse models, ouabain inhibited tumor metastases but did not alter the growth of subcutaneous tumors. Thus, we have identified a novel mechanism to sensitize resistant cells to anoikis and decrease tumor metastasis. These results suggest a potential mechanism for the observed clinical reduction in metastasis and relapse in breast cancer patients who have undergone treatments with cardiac glycosides.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation

Simpson

Mawji²,

Anyiwe³

et al. 2009

Cancer Research

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“…Strong evidence now supports the anticancer properties of these drugs. Early epidemiologic studies by Stenkvist et al reported significantly lower mortality rates of cancer patients under cardiac glycoside treatment (25,26). Because then, numerous in vitro studies have reported potent antiproliferative effects of these compounds in a panel of cancer cell lines, including breast (27), prostate (28), melanoma (29), pancreatic (30), lung (31), leukemia (32), neuroblastoma (33), and renal adenocarcinoma (ref.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening Identifies Cardiac Glycosides as Potent Inhibitors of Human Tissue Kallikrein Expression: Implications for Cancer Therapies

Prassas

Paliouras

Datti

et al. 2008

Clinical Cancer Research

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Purpose: Human tissue kallikreins (KLK) comprise a subgroup of 15 homologous secreted serine proteases. Primarily known for their clinical use as cancer biomarkers (e.g., PSA), KLKs have recently been directly implicated in cancer-related processes, including invasion, angiogenesis, and tumor growth regulation. Therefore, the identification of compounds that would modulate expression of KLKs might be of considerable therapeutic value. Experimental Design: A cell-based high-throughput screening (HTS) of three small molecule libraries (f4,500 compounds) was undertaken; KLK expression in the breast cancer cell line MDA-MB-468 was assessed with sensitive ELISAs. Results: The initial screening resulted in 66 ''putative hits'' that decreased KLK5 expression by at least 50% over control. Secondary screening and mini-dose-response assays resulted in 21 ''validated hits.'' These 21 compounds were clustered in only three distinct functional families and were further analyzed in vitro to determine their effectiveness (IC 50 s). Hits that failed to show dose-responsiveness or interfered with the viability of the cells were excluded. Multiple members of the cardiac glycoside family were found to be novel inhibitors of KLK expression, acting at low concentrations (10-50 nmol/L). Furthermore, members of the same family induced marked decreases in c-MYC and c-FOS expression, in a dose-dependent manner that correlated the KLK inhibition, suggesting a transcriptional mechanism of regulation of KLK expression. Conclusions: We conclude that cardiac glycosides can dramatically suppress the transcription of KLKs and that these effects may be linked to proto-oncogene (c-myc/fos) expression. These findings may partially explain the recently realized antineoplastic actions of cardiac glycosides.

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“…For many years, members of this family (digoxin, digitoxin) have been in clinical use for the treatment of heart failure and atrial arrhythmia (1). However, some early epidemiologic studies, describing significantly lower growth potential of tumors on patients on digitalis treatment, sparked new interest in the anticancer properties of these drugs (2).…”

Section: Introductionmentioning

confidence: 99%

Digitoxin-Induced Cytotoxicity in Cancer Cells Is Mediated through Distinct Kinase and Interferon Signaling Networks

Prassas

Karagiannis

Batruch

et al. 2011

Molecular Cancer Therapeutics

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Cardiac glycosides (e.g., digoxin, digitoxin) constitute a diverse family of plant-derived sodium pump inhibitors that have been in clinical use for the treatment of heart-related diseases (congestive heart failure, atrial arrhythmia) for many years. Recently though, accumulating in vitro and in vivo evidence highlight potential anticancer properties of these compounds. Despite the fact that members of this family have advanced to clinical trial testing in cancer therapeutics, their cytotoxic mechanism is not yet elucidated. In this study, we investigated the cytotoxic properties of cardiac glycosides against a panel of pancreatic cancer cell lines, explored their apoptotic mechanism, and characterized the kinetics of cell death induced by these drugs. Furthermore, we deployed a high-throughput kinome screening approach and identified several kinases of the Na-K-ATPase-mediated signal transduction circuitry (epidermal growth factor receptor, Src, pkC, and mitogen-activated protein kinases) as important mediators downstream of cardiac glycoside cytotoxic action. To further extend our knowledge on their mode of action, we used mass-spectrometry-based quantitative proteomics (stable isotope labeling of amino acids in cell culture) coupled with bioinformatics to capture large-scale protein perturbations induced by a physiological dose of digitoxin in BxPC-3 pancreatic cancer cells and identified members of the interferon family as key regulators of the main protein/protein interactions downstream of digitoxin action. Hence, our findings provide more in-depth information regarding the molecular mechanisms underlying cardiac glycoside-induced cytotoxicity. Mol Cancer Ther; 10(11); 2083-93. Ó2011 AACR.

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Cardiac Glycosides and Breast Cancer

Cited by 134 publications

References 0 publications

Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation

Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation

High-Throughput Screening Identifies Cardiac Glycosides as Potent Inhibitors of Human Tissue Kallikrein Expression: Implications for Cancer Therapies

Digitoxin-Induced Cytotoxicity in Cancer Cells Is Mediated through Distinct Kinase and Interferon Signaling Networks

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