Digitoxin medication and cancer; case control and internal dose-response studies

Haux, Johan; Klepp, O; Spigset, Olav; Tretli, Steinar

doi:10.1186/1471-2407-1-11

Cited by 125 publications

(113 citation statements)

References 19 publications

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“…The growing body of epidemiological (19,20), in vitro (18), and in vivo (31) evidence supporting the anticancer benefits of cardenolides has prompted the search for noncardioactive analogs that retain anticancer activity. The specific mechanism of cardenolide-induced cytotoxicity remains controversial.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to its well known cardiac activity, which is mediated by inhibition of the plasma membrane Na ϩ ͞K ϩ -ATPase (17), digitoxin has demonstrated in vitro anticancer properties (18), and patient profiling suggests the survival rate of cancer patients taking digitoxin is statistically enhanced (19,20). Cardiac glycosides were also recently noted to inhibit the expression of four genes that are overexpressed in prostate cancer cells, including transcription factors and the apoptosis inhibitor survivin (21), and to provide protective effects against polyglutamine-based diseases (22).…”

mentioning

confidence: 99%

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Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

Langenhan¹,

Peters²,

Guzei³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

218

174

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Glycosylated natural products are reliable platforms for the development of many front-line drugs, yet our understanding of the relationship between attached sugars and biological activity is limited by the availability of convenient glycosylation methods. When a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation is used, the glycorandomization of digitoxin leads to analogs that display significantly enhanced potency and tumor specificity and suggests a divergent mechanistic relationship between cardiac glycosideinduced cytotoxicity and Na ؉ ͞K ؉ -ATPase inhibition. This report highlights the remarkable advantages of glycorandomization as a powerful tool in glycobiology and drug discovery.carbohydrate ͉ natural product ͉ sugar

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

Langenhan¹,

Peters²,

Guzei³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

218

174

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show abstract

“…A review of plasma samples from 9271 cardiac patients revealed high concentrations of digitoxin were associated with a lower risk for leukemia, lymphoma and cancer of the urinary tract. 80 A number of in vitro studies have confirmed anti-cancer effects of digoxin and other glycosides (reviewed in 78,79). Based on these and other clinical and preclinical data, two trials involving digoxin have been initiated (Clinical Trials.gov NCT00281021 and NCT00650910).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Increases the Expression of Stem-Cell Markers and Promotes Clonogenicity in Glioblastoma Neurospheres

Bar

Lin

Mahairaki

et al. 2010

The American Journal of Pathology

314

293

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Hypoxia promotes the expansion of non-neoplastic stem and precursor cell populations in the normal brain, and is common in malignant brain tumors. We examined the effects of hypoxia on stem-like cells in glioblastoma (GBM). When GBM-derived neurosphere cultures are grown in 1% oxygen, hypoxia-inducible factor 1␣ (HIF1␣) protein levels increase dramatically, and mRNA encoding other hypoxic response genes, such as those encoding hypoxia-inducible gene-2, lysyl oxidase, and vascular endothelial growth factor, are induced over 10-fold. Hypoxia increases the stem-like side population over fivefold, and the percentage of cells expressing CD133 threefold or more. Notch pathway ligands and targets are also induced. The rise in the stem-like fraction in GBM following hypoxia is paralleled by a twofold increase in clonogenicity. We believe HIF1␣ plays a causal role in these changes, as when oxygen-stable HIF1␣ is expressed in normoxic glioma cells CD133 is induced. We used digoxin, which has been shown to lower HIF protein levels in vitro and in vivo, to inhibit the hypoxic response. Digoxin suppressed HIF1␣ protein expression, HIF1␣ downstream targets, and slowed tumor growth in vivo. In addition, pretreatment with digoxin reduced GBM flank xenograft engraftment of hypoxic GBM cells , and daily intraperitoneal injections of digoxin were able to significantly inhibit the growth of established subcutaneous glioblastoma xenografts , and suppressed expression of vascular endothelial growth factor.

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“…Use of various medications, such as antibiotics (20)(21)(22), nonsteroidal anti-inflammatory drugs and other analgesics (20,(23)(24)(25), corticosteroids and other immunosuppressants (20,23,(26)(27)(28)(29), histamine2 receptor antagonists (30,31), psychotropic drugs (20,28,32), anticonvulsants (33)(34)(35), estrogen replacement therapy (20,36), antidepressants or antianxiety drugs (37,38), amphetamines (38), and digitalis or digitoxin (20,39), has been associated with risk of nonHodgkin's lymphoma (NHL). However, to our knowledge, there is very little information on medication use and subsequent risks of multiple myeloma or other lymphoproliferative malignancies.…”

Section: Introductionmentioning

confidence: 99%

Risk of Multiple Myeloma following Medication Use and Medical Conditions: A Case-Control Study in Connecticut Women

Landgren

Zhang

Zahm

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Certain commonly used drugs and medical conditions characterized by chronic immune dysfunction and/or antigen stimulation have been suggested to affect important pathways in multiple myeloma tumor cell growth and survival. We conducted a population-based case-control study to investigate the role of medical history in the etiology of multiple myeloma among Connecticut women. Methods: A total of 179 incident multiple myeloma cases (21-84 years, diagnosed 1996-2002) and 691 population-based controls was included in this study. Information on medical conditions, medications, and medical radiation was obtained by in-person interviews. We calculated odds ratios (OR) as measures of relative risks using logistic regression models. Results: A reduced multiple myeloma risk was found among women who had used antilipid statin therapy [OR, 0.4; 95%

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Digitoxin medication and cancer; case control and internal dose-response studies

Abstract: Background: Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population.

Cited by 125 publications

References 19 publications

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

Hypoxia Increases the Expression of Stem-Cell Markers and Promotes Clonogenicity in Glioblastoma Neurospheres

Risk of Multiple Myeloma following Medication Use and Medical Conditions: A Case-Control Study in Connecticut Women

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