Skip to main content
SpringerLink
Log in
Book cover

Natural Products pp 3743–3755Cite as

Cardiac Glycosides and Anticancer Activity

  • Reference work entry
  • First Online:

Abstract

Cardiac glycosides (CGs) which are composed of aglycone moiety and glycone moiety occur mainly in plants. CGs increase cardiac contractility by inhibiting the sodium-potassium-adenosine triphosphatase (Na+/K+ ATPase) of plasma membrane and are widely used in the treatment of chronic heart failure. New findings within recent years have revealed that CGs are involved in selective control of tumor proliferation. Inhibition of Na+/K+ ATPase by CGs induces antiproliferative downstream effects which are related to cell growth and apoptosis. As anticancer effects of CGs occur also below their cardiotoxic concentration, Na+/K+ ATPase independent pathways are also proposed. Some CGs are almost completely nontoxic to rodent-derived tumor cell lines but potently inhibit proliferation human tumor cell lines. Some of the CGs, in nontoxic concentrations, are able to induce apoptosis in human promyelocytic leukemia cells (HL60) but not in normal leukocytes. The anticancer effects of CGs are found to be related to the inhibition of tissue kallikrein expression, anoikis sensitizers, inhibition on topoisomerase, blockade of NF-kB activation, and suppression of general protein synthesis. However, the viewpoint and evidence of CGs as anticancer agents in clinical application are still controversial.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   2,999.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   549.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

bcl-2:

B cell lymphoma/leukemia-2

Ca2+ :

Calcium ion

c-FOS:

FBJ osteosarcoma oncogene

CGs:

Cardiac glycosides

c-myc:

v-myc myelocytomatosis viral oncogene homolog (avian)

DNA:

Deoxyribonucleic acid

EDLC:

Endogenous digitalis-like compounds

ER:

Estrogen receptor

ERK:

Extracellular signal-regulated kinase

HL60:

Human promyelocytic leukemia cells

IkBa:

I kappa B alpha

JAK2:

Janus kinase 2

JNK:

c-Jun NH2-terminal kinase

KLK:

Kallikreins

MAPK:

Mitogen-activated protein kinase

MCF-7:

Michigan Cancer Foundation – 7

MEK:

MAPK/ERK kinase

mRNA:

Messenger ribose nucleic acid

Na+/Ca2+ exchanger:

Sodium-calcium exchanger

Na+/K+ ATPase:

Sodium-potassium-adenosine triphosphatase

NF-κB:

Nuclear factor kappa-light-chain enhancer of activated B cells

p21:

Protein 21

p53:

Protein 53 or tumor protein 53

PI3K:

Phosphoinositide-3 kinase

PPC-1:

Primary prostatic carcinoma cell line

PSA:

Prostate-specific antigen

PUMA:

p53 upregulated modulator of apoptosis

Rac1:

Ras-related C3 botulinum toxin substrate l

SCID:

Severe combined immune deficiency

Src:

Sarcoma

t1/2 :

Half-life

TNFR:

Tumor necrosis factor receptor

References

  1. Wang HYL, Xin WJ, Zhou MQ et al (2011) Stereochemical survey of digitoxin monosaccharides: new anti-cancer analogues with enhanced apoptotic activity and growth inhibitory effect on human non-small cell lung cancer cell. ACS Med Chem Lett 2:73–78

    Article  CAS  Google Scholar 

  2. Haas M, Askari A, Xie Z (2000) Involvement of Src and epidermal growth factor receptor in the signal-transducing function of Na+/K+-ATPase. J Biol Chem 275:27832–27837

    CAS  Google Scholar 

  3. Xie Z, Cai T (2003) Na+-K+-ATPase-mediated signal transduction: from protein interaction to cellular function. Mol Interv 3:157–168

    Article  CAS  Google Scholar 

  4. Arispe N, Diaz JC, Simakova O et al (2008) Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels. Proc Natl Acad Sci USA 105:2610–2615

    Article  CAS  Google Scholar 

  5. Christophe A, Carolyn K, Constantin R et al (2009) Revisiting old drugs as novel agents for retinoblastoma: in vitro and in vivo antitumor activity of cardenolides. IOVS 50:3065–3073

    Google Scholar 

  6. Raghavendra PB, Sreenivasan Y, Manna SK (2007) Oleandrin induces apoptosis in human, but not in murine cells: dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity. Mol Immunol 44:2292–2302

    Article  CAS  Google Scholar 

  7. Robert AN, Yang PY, Alison DP et al (2008) Cardiac glycosides as novel cancer therapeutic agents. Mol Interv 8:36–49

    Article  Google Scholar 

  8. Yang PY, Menter DG (2009) Carrie Cartwright, et al. Oleandrin-mediated inhibition of human tumor cell proliferation: importance of Na, K-ATPase α subunits as drug targets. Mol Cancer Ther 8:2319–2328

    Article  CAS  Google Scholar 

  9. O’Brien WJ, Lingrel JB, Wallick ET (1994) Ouabain binding kinetics of the rat alpha two and alpha 3 isoforms of the sodium-potassium adenosine triphosphate. Arch Biochem Biophys 310:32–39

    Article  Google Scholar 

  10. Sakai H, Suzuki T, Maeda M et al (2004) Up-regulation of Na+, K+-ATPase in -3-isoform and down-regulation of the α 1-isoform in human colorectal cancer. FEBS Lett 563:151–154

    Article  CAS  Google Scholar 

  11. Sreenivasan Y, Sarkar A, Manna SK (2003) Oleandrin suppresses activation of nuclear transcription factor-kB and activator protein-1 and potentiates apoptosis induced by ceramide. Biochem Pharmacol 66:2223–2239

    Article  CAS  Google Scholar 

  12. Verheye-Dua F, Bohm L (1998) Na+, K+-ATPase inhibitor, ouabain accentuates irradiation damage in human tumour cell lines. Radiat Oncol Investig 6:109–119

    Article  CAS  Google Scholar 

  13. Krzysztof B, Katarzyna W, Anna B (2006) Inhibition of DNA topoisomerases I and II, and growth inhibition of breast cancer MCF-7 cells by Ouabain, Digoxin and Proscillaridin. A Biol Pharm Bull 29:1493–1497

    Article  Google Scholar 

  14. Katarzyna W, Krzysztof B, Anna B (2006) CGs in cancer research and cancer therapy. Acta Poloniae Pharmaceutica—Drug Res 63:109–115

    Google Scholar 

  15. Sreenivasan Y, Raghavendra PB, Manna SK (2006) Oleandrin mediated expression of Fas potentiates apoptosis in tumor cells. J Clin Immunol 26:308–322

    Article  CAS  Google Scholar 

  16. Frese S, Frese SM, Anne CA et al (2006) CGs initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5. Cancer Res 66:6867–5874

    Article  Google Scholar 

  17. Wang Z, Zheng M, Li ZC et al (2009) CGs inhibit p53 synthesis by a mechanism relieved. Cancer Res 69:6556–6564

    Article  CAS  Google Scholar 

  18. Bouchet BP, de Fromentel CC, Puisieux A et al (2006) p53 as a target for anticancer drug development. Crit Rev Oncol Hematol 58:190–207

    Article  Google Scholar 

  19. Kaelin WG (2005) The concept of synthetic lethality in the context of anti-cancer therapy. Nat Rev Cancer 5:689–698

    Article  CAS  Google Scholar 

  20. Ioannis P, Miltiadis P, Alessandro D et al (2008) High throughput screening identifies cardiac glycosides as potent inhibitors of human tissue Kallikrein expression: implications for cancer therapies. Clin Cancer Res 14:5778–5784

    Article  Google Scholar 

  21. Craig DS, Imtiaz AM, Kika A et al (2009) Inhibition of the sodium potassium adenosine triphosphatase pump sensitizes cancer cells to anoikis and prevents distant tumor formation. Cancer Res 69:2739–2747

    Article  Google Scholar 

  22. Walker JV, Nitiss JL (2002) DNA topoisomerase II as a target for cancer chemotherapy. Cancer Invest 20:570–589

    Article  CAS  Google Scholar 

  23. Fortune JM, Osheroff N (2000) Topoisomerase II as a target for anti-cancer drugs: when enzymes stop being nice. Prog Nucl Res Mol Biol 64:221–253

    Article  CAS  Google Scholar 

  24. Sen R, Baltimore D (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46:705–716

    Article  CAS  Google Scholar 

  25. Sunil KM, Nand KS, Robert AN et al (2000) Oleandrin suppresses activation of nuclear transcription factor-κB, activator protein-1, and c-Jun NH2-terminal kinase1. Cancer Res 60:3838–3847

    Google Scholar 

  26. Yang QF, Huang W, Catherine J et al (2005) CGs inhibit TNF-α/NF-κB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor. Proc Natl Acad Sci USA 102:9631–9636

    Article  CAS  Google Scholar 

  27. Andrea P, Markus KM, Magdalena S et al (2009) Cardiac glycosides induce cell death in human cells by inhibiting general protein synthesis. PLoS One 4:e8292

    Article  Google Scholar 

  28. Thomas PA, Timothy LL, Henrik TS et al (2008) Digoxin treatment is associated with an increased incidence of breast cancer: a population-based case-control study. Breast Cancer Res 10:R102

    Article  Google Scholar 

  29. Tatjana M, Eric VQ, Bruno D et al (2007) Cardiotonic steroids on the road to anti-cancer therapy. Biochim Biophys Acta 1776:32–57, 29–31

    Google Scholar 

  30. Stenkvist B, Bengtsson E, Eriksson O et al (1979) CGs and breast cancer. Lancet 1:563

    Article  CAS  Google Scholar 

  31. Stenkvist B (1999) Is digitalis a therapy for breast carcinoma? Oncol Rep 6:493–496

    CAS  Google Scholar 

  32. Haux J, Klepp O, Spigset O et al (2001) Digitoxin medication and cancer; case control and internal dose-response studies. BMC Cancer 1:11

    Article  CAS  Google Scholar 

  33. Biggar RJ (2012) Molecular pathways: Digoxin use and estrogen-sensitive cancers: risks and possible therapeutic implications. Clin Cancer Res 18:2133–2137

    Article  CAS  Google Scholar 

  34. Hosam AE, Todd AS, William T et al (2012) Digitoxin and its analogs as novel cancer therapeutics. Exp Hematol Oncol 1:4

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Dalian Medical University, Dalian, 116044, China

    Prof. Yuan Lin, Dapeng Chen, Li Wang & Dongmei Ye

  2. College of Medicine, Chifeng University, Inner Mongolia, 024000, China

    Dongmei Ye

Authors
  1. Prof. Yuan Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dapeng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dongmei Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuan Lin .

Editor information

Editors and Affiliations

  1. Botany Department, M.L. Sukhadia University, Durga Nursery Road, Udaipur, 313001, Rajasthan, India

    Kishan Gopal Ramawat

  2. Institute of Vine and Wine Sciences, Biological-Active Plant Substances Study, University of Bordeaux, 210 Chemin de Leysotte CS 50008, Villenave d'Ornon, 33882, France

    Jean-Michel Mérillon

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this entry

Cite this entry

Lin, Y., Chen, D., Wang, L., Ye, D. (2013). Cardiac Glycosides and Anticancer Activity. In: Ramawat, K., Mérillon, JM. (eds) Natural Products. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-22144-6_159

Download citation

Publish with us

Policies and ethics

Search

Navigation