Digitoxin and its analogs as novel cancer therapeutics

A growing body of evidence indicates that digitoxin cardiac glycoside is a promising anticancer agent when used at therapeutic concentrations. Digitoxin has a prolonged half-life and a well-established clinical profile. New scientific avenues have shown that manipulating the chemical structure of the saccharide moiety of digitoxin leads to synthetic analogs with increased cytotoxic activity. However, the anticancer mechanism of digitoxin or synthetic analogs is still subject to study while concerns about digitoxin's cardiotoxicity preclude its clinical application in cancer therapeutics. This review focuses on digitoxin and its analogs, and their cytotoxicity against cancer cells. Moreover, a new perspective on the pharmacological aspects of digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.

[1]  A. Egloff,et al.  Evaluation of Anticyclin B1 Serum Antibody as a Diagnostic and Prognostic Biomarker for Lung Cancer , 2005, Annals of the New York Academy of Sciences.

[2]  Johannes Rinn,et al.  Ras/Erk MAPK Signaling in Epidermal Homeostasis and Neoplasia , 2007, Cell cycle.

[3]  H. Brewer Historical perspectives on health , 2004, The journal of the Royal Society for the Promotion of Health.

[4]  R. Huxtable The erroneous pharmacology of a cat. , 2001, Molecular Interventions.

[5]  J. M. Langenhan,et al.  Modifying the glycosidic linkage in digitoxin analogs provides selective cytotoxins. , 2008, Bioorganic & medicinal chemistry letters.

[6]  M. López-Lázaro Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved , 2007, Expert opinion on therapeutic targets.

[7]  A. Multani,et al.  AnvirzelTM, an extract of Nerium oleander, induces cell death in human but not murine cancer cells , 2000, Anti-cancer drugs.

[8]  S. Wheatley,et al.  Liaisons between Survivin and Plk1 during Cell Division and Cell Death , 2010, The Journal of Biological Chemistry.

[9]  T. Smith Digitalis toxicity: epidemiology and clinical use of serum concentration measurements. , 1975, The American journal of medicine.

[10]  S. Rahimtoola,et al.  The use of digitalis in heart failure. , 1996, Current problems in cardiology.

[11]  Y. Rojanasakul,et al.  Stereochemical survey of digitoxin monosaccharides: new anticancer analogues with enhanced apoptotic activity and growth inhibitory effect on human non-small cell lung cancer cell. , 2011, ACS medicinal chemistry letters.

[12]  R. Götz,et al.  Inter-cellular adhesion disruption and the RAS/RAF and beta-catenin signalling in lung cancer progression , 2008, Cancer Cell International.

[13]  Tak W. Mak,et al.  Pathways of apoptotic and non-apoptotic death in tumour cells , 2004, Nature Reviews Cancer.

[14]  H. Schatzmann,et al.  [Inhibition of the active Na-K-transport and Na-K-activated membrane ATP-ase of erythrocyte stroma by ouabain]. , 1965, Helvetica physiologica et pharmacologica acta.

[15]  K. Winnicka,et al.  Apoptosis-mediated cytotoxicity of ouabain, digoxin and proscillaridin A in the estrogen independent MDA-MB-231 breast cancer cells , 2007, Archives of pharmacal research.

[16]  J. Kaplan Membrane cation transport and the control of proliferation of mammalian cells. , 1978, Annual review of physiology.

[17]  T. Lawrence Ouabain sensitizes tumor cells but not normal cells to radiation. , 1987, International journal of radiation oncology, biology, physics.

[18]  Abe. J. Goldin,et al.  DIGITALIS AND CANCER , 1984, The Lancet.

[19]  J. Chambard,et al.  ERK and cell death: Mechanisms of ERK‐induced cell death – apoptosis, autophagy and senescence , 2010, The FEBS journal.

[20]  P. Khavari,et al.  Erk1/2 MAP kinases are required for epidermal G2/M progression , 2009, The Journal of cell biology.

[21]  J. Hartley,et al.  Cardiac glycosides inhibit TNF-alpha/NF-kappaB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Fengzhi Li,et al.  Control of apoptosis and mitotic spindle checkpoint by survivin , 1998, Nature.

[23]  L. Nutt,et al.  Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. , 2000, Cancer research.

[24]  T. Yoshida,et al.  Bufalin induces apoptosis and influences the expression of apoptosis-related genes in human leukemia cells. , 1995, Leukemia research.

[25]  E. Bengtsson,et al.  Cardiac glycosides and breast cancer, revisited. , 1982, The New England journal of medicine.

[26]  S. Weed,et al.  Regulation of c-SRC Activity and Function by the Adapter Protein CAS , 2000, Molecular and Cellular Biology.

[27]  Fengzhi Li,et al.  Pleiotropic cell-division defects and apoptosis induced by interference with survivin function , 1999, Nature Cell Biology.

[28]  Dong-Hoon Kim Prognostic Implications of Cyclin B1, p34cdc2, p27Kip1 and p53 Expression in Gastric Cancer , 2007, Yonsei medical journal.

[29]  S. Manna,et al.  Oleandrin suppresses activation of nuclear transcription factor-kappa B and activator protein-1 and potentiates apoptosis induced by ceramide. , 2003, Biochemical pharmacology.

[30]  A. Fornace,et al.  p38 MAP kinase's emerging role as a tumor suppressor. , 2004, Advances in cancer research.

[31]  Derek K. Rogalsky,et al.  A Direct Comparison of the Anticancer Activities of Digitoxin MeON-Neoglycosides and O-Glycosides: Oligosaccharide Chain Length-Dependent Induction of Caspase-9-Mediated Apoptosis. , 2010, ACS medicinal chemistry letters.

[32]  W. Hittelman,et al.  Oleandrin-mediated oxidative stress in human melanoma cells. , 2006, Journal of experimental therapeutics & oncology.

[33]  T. Yoshida,et al.  Bufalin reduces the level of topoisomerase II in human leukemia cells and affects the cytotoxicity of anticancer drugs. , 1997, Leukemia research.

[34]  F. Hoffmann,et al.  Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  N. Perkins,et al.  Retracted: A cell cycle regulatory network controlling NF‐κB subunit activity and function , 2007, The EMBO journal.

[36]  J. Medina-Franco,et al.  The prince and the pauper. A tale of anticancer targeted agents , 2008, Molecular Cancer.

[37]  E. Grande,et al.  The dual kinase complex FAK-Src as a promising therapeutic target in cancer , 2010, OncoTargets and therapy.

[38]  Lijun Liu,et al.  On the importance and mechanism of amplification of digitalis signal through Na+/K+-ATPase. , 2006, Cellular and molecular biology.

[39]  Zijian Xie,et al.  Na+-K+--ATPase-mediated signal transduction: from protein interaction to cellular function. , 2003, Molecular interventions.

[40]  David I. Smith,et al.  Genome‐wide gene expression profiling of cervical cancer in Hong Kong women by oligonucleotide microarray , 2006, International journal of cancer.

[41]  Jun O. Liu,et al.  Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth , 2008, Proceedings of the National Academy of Sciences.

[42]  K. Chou,et al.  Tamoxifen-Induced Increases in Cytoplasmic Free Ca2+ Levels in Human Breast Cancer Cells , 2004, Breast Cancer Research and Treatment.

[43]  B. Tombal,et al.  Role of store-dependent influx of Ca2+ and efflux of K+ in apoptosis of CHO cells. , 2004, Cell calcium.

[44]  Y. Nakagawa,et al.  Role of calcium-induced mitochondrial hydroperoxide in induction of apoptosis of RBL2H3 cells with eicosapentaenoic acid treatment , 2005, Free radical research.

[45]  I. Larre,et al.  Ouabain Binding to Na+,K+-ATPase Relaxes Cell Attachment and Sends a SpecificSignal (NACos) to the Nucleus , 2004, The Journal of Membrane Biology.

[46]  B. Zhivotovsky,et al.  Death through a tragedy: mitotic catastrophe , 2008, Cell Death and Differentiation.

[47]  B. Gabrielli,et al.  Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events. , 2000, Experimental cell research.

[48]  R. Agami,et al.  Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension , 2003, The EMBO journal.

[49]  M. Watabe,et al.  Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells , 1999, Oncogene.

[50]  G Eklund,et al.  Evidence of a modifying influence of heart glucosides on the development of breast cancer. , 1980, Analytical and quantitative cytology.

[51]  G. O'Doherty,et al.  The de novo synthesis of oligosaccharides: application to the medicinal chemistry SAR-study of digitoxin. , 2008, Current topics in medicinal chemistry.

[52]  Lijun Liu,et al.  Digitalis-Induced Signaling by Na+/K+-ATPase in Human Breast Cancer Cells , 2005, Molecular Pharmacology.

[53]  G. Stark,et al.  Control of the G2/M transition , 2006, Molecular biotechnology.

[54]  J. Lingrel,et al.  Characterization of the human Na,K-ATPase alpha 2 gene and identification of intragenic restriction fragment length polymorphisms. , 1989, The Journal of biological chemistry.

[55]  E. Lewinn CARDIAC GLYCOSIDES AND BREAST CANCER , 1979, The Lancet.

[56]  N. K. Sah,et al.  Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase. , 2000, Cancer research.

[57]  O. Shiratori GROWTH INHIBITORY EFFECT OF CARDIAC GLYCOSIDES AND AGLYCONES ON NEOPLASTIC CELLS , 1967 .

[58]  Jiang Tian,et al.  Na/K-ATPase tethers phospholipase C and IP3 receptor into a calcium-regulatory complex. , 2005, Molecular biology of the cell.

[59]  S. Manna,et al.  Retraction Note: Oleandrin-Mediated Expression of Fas Potentiates Apoptosis in Tumor Cells , 2006, Journal of Clinical Immunology.

[60]  P. S. Wang,et al.  Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells. , 2001, The Journal of urology.

[61]  A. Marchetti,et al.  Survivin gene expression in early‐stage non‐small cell lung cancer , 2003, The Journal of pathology.

[62]  K. Zinkiewicz,et al.  Assessment of prognostic significance of cytoplasmic survivin expression in advanced oesophageal cancer. , 2004, Folia histochemica et cytobiologica.

[63]  M. Karamouzis,et al.  The Activator Protein-1 Transcription Factor in Respiratory Epithelium Carcinogenesis , 2007, Molecular Cancer Research.

[64]  C. Duckett,et al.  Acute Ablation of Survivin Uncovers p53-dependent Mitotic Checkpoint Functions and Control of Mitochondrial Apoptosis* , 2004, Journal of Biological Chemistry.

[65]  R. Sutherland,et al.  Expression and prognostic significance of cyclin B1 and cyclin A in non‐small cell lung cancer , 2009, Histopathology.

[66]  J. Williams,et al.  Effects of arrhythmia-producing concentrations of digitoxin on mechanical performance of cat myocardium. , 1983, American heart journal.

[67]  Jiri Bartek,et al.  Targeting the checkpoint kinases: chemosensitization versus chemoprotection , 2004, Nature Reviews Cancer.

[68]  J. Haux Digitoxin is a potential anticancer agent for several types of cancer. , 1999, Medical hypotheses.

[69]  H. Kuwano,et al.  The clinical significance of Cyclin B1 and Wee1 expression in non-small-cell lung cancer. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[70]  Shaomeng Wang,et al.  Cardiac glycosides inhibit p53 synthesis by a mechanism relieved by Src or MAPK inhibition. , 2009, Cancer research.

[71]  C. Ling,et al.  Anti-tumor activities and apoptosis-regulated mechanisms of bufalin on the orthotopic transplantation tumor model of human hepatocellular carcinoma in nude mice. , 2007, World journal of gastroenterology.

[72]  R. Newman,et al.  Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin. , 2001, Biochemical pharmacology.

[73]  Y. Rojanasakul,et al.  C5'-Alkyl Substitution Effects on Digitoxigenin α-l-Glycoside Cancer Cytotoxicity. , 2011, ACS medicinal chemistry letters.

[74]  Jean-Luc Coll,et al.  Targeting cyclin B1 through peptide-based delivery of siRNA prevents tumour growth , 2009, Nucleic acids research.

[75]  S. Stacker,et al.  Targeting lymphatic vessel functions through tyrosine kinases , 2010, Journal of angiogenesis research.

[76]  Y. Kondo,et al.  Autophagic Cell Death of Human Pancreatic Tumor Cells Mediated by Oleandrin, a Lipid-Soluble Cardiac Glycoside , 2007, Integrative cancer therapies.

[77]  D. Bell-Pedersen,et al.  A connection between MAPK pathways and circadian clocks , 2008, Cell cycle.

[78]  G. Gorbsky,et al.  Survivin dynamics increases at centromeres during G2/M phase transition and is regulated by microtubule-attachment and Aurora B kinase activity , 2004, Journal of Cell Science.

[79]  C. Sheline,et al.  Apoptotic insults impair Na+, K+-ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress. , 2003, Journal of cell science.

[80]  S. Azrak,et al.  Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients. , 2005, Journal of natural products.

[81]  M. Gheorghiade,et al.  Contemporary Use of Digoxin in the Management of Cardiovascular Disorders , 2006, Circulation.

[82]  M. Medarde,et al.  A Short Review on Cardiotonic Steroids and Their Aminoguanidine Analogues , 2000 .

[83]  L. Milas,et al.  Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process. , 2002, Cancer letters.

[84]  Liying Wang,et al.  Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells. , 2012, Toxicology and applied pharmacology.

[85]  M. Inoue,et al.  Structure-cytotoxic activity relationship for the toad poison bufadienolides. , 1998, Bioorganic & medicinal chemistry.

[86]  A. Rajasekaran,et al.  Novel role for Na,K-ATPase in phosphatidylinositol 3-kinase signaling and suppression of cell motility. , 2005, Molecular biology of the cell.

[87]  Massimo Milione,et al.  Src family kinase activity regulates adhesion, spreading and migration of pancreatic endocrine tumour cells. , 2007, Endocrine-related cancer.

[88]  Eleftherios P. Diamandis,et al.  Novel therapeutic applications of cardiac glycosides , 2008, Nature Reviews Drug Discovery.

[89]  W. Zidek,et al.  Proscillaridin A immunoreactivity: its purification, transport in blood by a specific binding protein and its correlation with blood pressure. , 1998, Clinical and experimental hypertension.

[90]  X. Wang,et al.  LC/MS/MS analyses of an oleander extract for cancer treatment. , 2000, Analytical chemistry.

[91]  K. Breithaupt-Grögler,et al.  Treatment of congestive heart failure - current status of use of digitoxin , 2001 .

[92]  M. Masnyk,et al.  The lead structure in cardiac glycosides is 5 beta, 14 beta-androstane-3 beta 14-diol. , 1985, Naunyn-Schmiedeberg's archives of pharmacology.

[93]  Y. Rojanasakul,et al.  Synthesis and Evaluation of the α-d-/α-l-Rhamnosyl and Amicetosyl Digitoxigenin Oligomers as Antitumor Agents , 2011 .

[94]  Alain C. Mita,et al.  Survivin: Key Regulator of Mitosis and Apoptosis and Novel Target for Cancer Therapeutics , 2008, Clinical Cancer Research.

[95]  J. Kaplan,et al.  Biochemistry of Na,K-ATPase. , 2002, Annual review of biochemistry.

[96]  J. Hartley,et al.  Cardiac glycosides inhibit TNF-α/NF-κB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor , 2005 .

[97]  B. Kahn,et al.  Multiple Signal Transduction Pathways Link Na+/K+-ATPase to Growth-related Genes in Cardiac Myocytes , 1998, The Journal of Biological Chemistry.

[98]  K. Strebhardt,et al.  Cyclin B1 depletion inhibits proliferation and induces apoptosis in human tumor cells , 2004, Oncogene.

[99]  T. Padilla-Benavides,et al.  Ouabain modulates epithelial cell tight junction , 2010, Proceedings of the National Academy of Sciences.

[100]  K. Milde-Langosch,et al.  Expression pattern of the AP-1 family in endometrial cancer: correlations with cell cycle regulators , 2001, Journal of Cancer Research and Clinical Oncology.

[101]  Paulus S. Wang,et al.  Effects of bufalin and cinobufagin on the proliferation of androgen dependent and independent prostate cancer cells , 2003, The Prostate.

[102]  S. Keyse,et al.  Dual-specificity MAP kinase phosphatases (MKPs) and cancer , 2008, Cancer and Metastasis Reviews.

[103]  U. Bavendiek,et al.  Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis? , 2009, Atherosclerosis.

[104]  L. Bohlin,et al.  Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs. , 2009, Journal of natural products.

[105]  A. Askari,et al.  Partial Inhibition of Na/K-ATPase by Ouabain Induces the Ca-dependent Expressions of Early-response Genes in Cardiac Myocytes (*) , 1996, The Journal of Biological Chemistry.

[106]  I. Gelman,et al.  SSeCKS/Gravin/AKAP12 attenuates expression of proliferative and angiogenic genes during suppression of v-Src-induced oncogenesis , 2006, BMC Cancer.

[107]  S. Manna,et al.  Oleandrin induces apoptosis in human, but not in murine cells: dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity. , 2007, Molecular immunology.

[108]  Zijian Xie,et al.  Role of Protein Kinase C in the Signal Pathways That Link Na+/K+-ATPase to ERK1/2* , 2001, The Journal of Biological Chemistry.

[109]  H. Mukhtar,et al.  Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin. , 2004, Toxicology and applied pharmacology.

[110]  K. Winnicka,et al.  Inhibition of DNA topoisomerases I and II, and growth inhibition of breast cancer MCF-7 cells by ouabain, digoxin and proscillaridin A. , 2006, Biological & pharmaceutical bulletin.

[111]  Takemi Yoshida,et al.  Selective Inhibitory Effect of Bufalin on Growth of Human Tumor Cells in vitro: Association with the Induction of Apoptosis in Leukemia HL‐60 Cells , 1994, Japanese journal of cancer research : Gann.

[112]  B. Stenkvist Is digitalis a therapy for breast carcinoma? , 1999, Oncology reports.

[113]  K. Winnicka,et al.  Dual effects of ouabain, digoxin and proscillaridin A on the regulation of apoptosis in human fibroblasts , 2010, Natural product research.

[114]  J. Casanova,et al.  FAK Regulates Intestinal Epithelial Cell Survival and Proliferation during Mucosal Wound Healing , 2011, PloS one.

[115]  M. Watabe,et al.  The Cooperative Interaction of Two Different Signaling Pathways in Response to Bufalin Induces Apoptosis in Human Leukemia U937 Cells* , 1996, The Journal of Biological Chemistry.

[116]  Jiri Bartek,et al.  Chk1 and Chk2 kinases in checkpoint control and cancer. , 2003, Cancer cell.

[117]  Robert A Newman,et al.  Cardiac glycosides as novel cancer therapeutic agents. , 2008, Molecular interventions.

[118]  J. Shapiro,et al.  Intracellular Reactive Oxygen Species Mediate the Linkage of Na+/K+-ATPase to Hypertrophy and Its Marker Genes in Cardiac Myocytes* , 1999, The Journal of Biological Chemistry.

[119]  Peiqing Sun,et al.  The pathways to tumor suppression via route p38. , 2007, Trends in biochemical sciences.

[120]  Y. Hasin,et al.  Sodium Pump Inhibition, Enhanced Calcium Influx via Sodium‐Calcium Exchange, and Positive Inotropic Response in Cultured Heart Cells , 1985, Circulation research.

[121]  Radhey S. Gupta,et al.  Cellular basis for the species differences in sensitivity to cardiac glycosides (digitalis) , 1986, Journal of cellular physiology.

[122]  Jiang Tian,et al.  Functional Characterization of Src-interacting Na/K-ATPase Using RNA Interference Assay* , 2006, Journal of Biological Chemistry.

[123]  K. Winnicka,et al.  Antiproliferative activity of derivatives of ouabain, digoxin and proscillaridin A in human MCF-7 and MDA-MB-231 breast cancer cells. , 2008, Biological & pharmaceutical bulletin.

[124]  Lijun Liu,et al.  Role of caveolae in ouabain-induced proliferation of cultured vascular smooth muscle cells of the synthetic phenotype. , 2004, American journal of physiology. Heart and circulatory physiology.

[125]  Hung-Jen Liu,et al.  Apoptosis induction in BEFV-infected Vero and MDBK cells through Src-dependent JNK activation regulates caspase-3 and mitochondria pathways , 2009, Veterinary research.

[126]  M. Suraokar,et al.  Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets , 2008, Molecular Cancer Therapeutics.

[127]  Jiang Tian,et al.  Src-mediated Inter-receptor Cross-talk between the Na+/K+-ATPase and the Epidermal Growth Factor Receptor Relays the Signal from Ouabain to Mitogen-activated Protein Kinases* , 2002, The Journal of Biological Chemistry.

[128]  Jian Zhang,et al.  Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[129]  Kyungeun Kim,et al.  Overexpressions of Cyclin B1, cdc2, p16 and p53 in Human Breast Cancer: The Clinicopathologic Correlations and Prognostic Implications , 2011, Yonsei medical journal.

[130]  Guido Kroemer,et al.  Cell death by mitotic catastrophe: a molecular definition , 2004, Oncogene.

[131]  G. Scheiner-Bobis,et al.  Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth. , 2007, American journal of physiology. Cell physiology.

[132]  O. Shiratori Growth inhibitory effect of cardiac glycosides and aglycones on neoplastic cells: in vitro and in vivo studies. , 1967, Gan.

[133]  K. Breithaupt-Grögler,et al.  Treatment of congestive heart failure – current status of use of digitoxin , 2001, European journal of clinical investigation.

[134]  A. Røseth,et al.  Prolonged digitoxin half-life in very elderly patients. , 1998, Age and ageing.

[135]  L. Bohlin,et al.  Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells , 2001, Anti-cancer drugs.