Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

The in vivo antitumor activity of cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact

Oncogene volume 33, pages 2947–2948 (2014)Cite this article

Subjects

In a recent paper published in Oncogene, Tailler et al.1 identified the cardiac glycoside ouabain as a potential antileukemic compound. They observed that ouabain was highly efficient in inhibiting the growth of human acute myeloid leukemia cells xenotransplanted in immunodeficient mice, without exerting significant toxicity on the host. The authors concluded that ouabain was a promising antileukemic agent whose activity should be evaluated in prospective clinical studies.

It has been known for some time that rodent cells are extremely more resistant than human cells to the cytotoxic effects of cardiac glycosides (both cardenolides and bufadienolides).2 Indeed, rodent cells were found to be over 100 times more resistant than human cells to the cytotoxic activity of all tested cardiac glycosides, including ouabain.2 This means that the anticancer effects induced by cardiac glycosides in mice harboring human cancer cells are probably due to interspecies differences in sensitivity and not to selective inhibition of tumor growth. In other words, the marked reduction in tumor growth observed when human cancer cells are xenografted into immune-deficient mice is probably caused by the ability of cardiac glycosides to kill human cells versus rodent cells rather than by their ability to kill cancer cells versus normal cells. We detected this experimental artifact in a PNAS paper, in which the cardiac glycoside digoxin was shown to induce a potent inhibition of tumor growth in mice xenografted with human cancer cells.3, 4 Our Letter to the Editor failed to reach many authors, reviewers and editors, as numerous papers containing this probable experimental artifact have been published since then.1, 5, 6, 7, 8, 9, 10

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Tailler M, Senovilla L, Lainey E, Thepot S, Metivier D, Sebert M et al. Antineoplastic activity of ouabain and pyrithione zinc in acute myeloid leukemia. Oncogene 2012; 31: 3536–3546.

    Article  CAS  Google Scholar 

  2. Gupta RS, Chopra A, Stetsko DK . Cellular basis for the species differences in sensitivity to cardiac glycosides (digitalis). J Cell Physiol 1986; 127: 197–206.

    Article  CAS  Google Scholar 

  3. Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci USA 2008; 105: 19579–19586.

    Article  CAS  Google Scholar 

  4. Lopez-Lazaro M . Digoxin, HIF-1, and cancer. Proc Natl Acad Sci USA 2009; 106: E26.

    Article  CAS  Google Scholar 

  5. Badr CE, Wurdinger T, Nilsson J, Niers JM, Whalen M, Degterev A et al. Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand and induces an alternative cell death pathway. Neuro Oncol 2011; 13: 1213–1224.

    Article  CAS  Google Scholar 

  6. Hiyoshi H, Abdelhady S, Segerstrom L, Sveinbjornsson B, Nuriya M, Lundgren TK et al. Quiescence and gammaH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase. Br J Cancer 2012; 106: 1807–1815.

    Article  CAS  Google Scholar 

  7. Xie XB, Yin JQ, Wen LL, Gao ZH, Zou CY, Wang J et al. Critical role of heat shock protein 27 in bufalin-induced apoptosis in human osteosarcomas: a proteomic-based research. PLoS One 2012; 7: e47375.

    Article  CAS  Google Scholar 

  8. Zhang DM, Liu JS, Tang MK, Yiu A, Cao HH, Jiang L et al. Bufotalin from Venenum Bufonis inhibits growth of multidrug resistant HepG2 cells through G2/M cell cycle arrest and apoptosis. Eur J Pharmacol 2012; 692: 19–28.

    Article  CAS  Google Scholar 

  9. Cheng CF, Lu IH, Tseng HW, Sun CY, Lin LT, Kuo ZK et al. Antitumor effect of periplocin in TRAIL-resistant human hepatocellular carcinoma cells through downregulation of IAPs. Evid Based Complement Alternat Med 2013; 2013: 958025.

    Google Scholar 

  10. Zhang DM, Liu JS, Deng LJ, Chen MF, Yiu A, Cao HH et al. Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway. Carcinogenesis (e-pub ahead of print 11 March 2013; doi:10.1093/carcin/bgt060).

    Article  CAS  Google Scholar 

  11. Lopez-Lazaro M . Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved. Expert Opin Ther Targets 2007; 11: 1043–1053.

    Article  CAS  Google Scholar 

  12. Calderon-Montaño JM, Burgos-Morón E, López-Lázaro M . Comment on ‘Quiescence and γcH2AX in neuroblastoma are regulated by Ouabain/Na,K-ATPase’: ouabain and cancer. Br J Cancer 2013; 108: 2189–2190.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain

    J M Calderón-Montaño, E Burgos-Morón & M López-Lázaro

Authors
  1. J M Calderón-Montaño
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Burgos-Morón
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M López-Lázaro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M López-Lázaro.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Calderón-Montaño, J., Burgos-Morón, E. & López-Lázaro, M. The in vivo antitumor activity of cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact. Oncogene 33, 2947–2948 (2014). https://doi.org/10.1038/onc.2013.229

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.229

This article is cited by

Search

Advanced search

Quick links