Cytotoxicity of glucoevatromonoside alone and in combination with chemotherapy drugs and their effects on Na+,K+-ATPase and ion channels on lung cancer cells


Cardiac glycosides (CGs) are useful drugs to treat cardiac illnesses and have potent cytotoxic and anticancer effects in cultured cells and animal models. Their receptor is the Na+,K+ ATPase, but other plasma membrane proteins might bind CGs as well. Herein, we evaluated the short- and long-lasting cytotoxic effects of the natural cardenolide glucoevatromonoside (GEV) on non-small-cell lung cancer H460 cells. We also tested GEV effects on Na+,K+ -ATPase activity and membrane currents, alone or in combination with selected chemotherapy drugs. GEV reduced viability, migration, and invasion of H460 cells spheroids. It also induced cell cycle arrest and death and reduced the clonogenic survival and cumulative population doubling. GEV inhibited Na+,K+-ATPase activity on A549 and H460 cells and purified pig kidney cells membrane. However, it showed no activity on the human red blood cell plasma membrane. Additionally, GEV triggered a Cl-mediated conductance on H460 cells without affecting the transient voltage-gated sodium current. The administration of GEV in combination with the chemotherapeutic drugs paclitaxel (PAC), cisplatin (CIS), irinotecan (IRI), and etoposide (ETO) showed synergistic antiproliferative effects, especially when combined with GEV + CIS and GEV + PAC. Taken together, our results demonstrate that GEV is a potential drug for cancer therapy because it reduces lung cancer H460 cell viability, migration, and invasion. Our results also reveal a link between the Na+,K+-ATPase and Clion channels.

Graphic Abstract

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9


  1. 1.

    Zappa C, Mousa SA (2016) Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res 5:288–300.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Popper HH (2016) Progression and metastasis of lung cancer. Cancer Metastasis Rev 35:75–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Menger L, Vacchelli E, Kepp O et al (2013) Trial watch Cardiac glycosides and cancer therapy Trial watch. Oncoimmunology 1:e23082.

    Article  Google Scholar 

  4. 4.

    Prassas I, Diamandis EP (2008) Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 7:926–935.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Slingerland M, Cerella C, Guchelaar HJ et al (2013) Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials. Invest New Drugs 31:1087–1094.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Reddy D, Ghosh P, Barh D et al (2020). Anticancer and Antiviral Properties of Cardiac Glycosides : A Review to Explore The Mechanism of Actions.

    Article  Google Scholar 

  7. 7.

    Gonçalves-de-albuquerque CF, Silva AR, Ign C, Castro-faria-neto HC (2017) Na/ K Pump and Beyond : Na/K-ATPase as a Modulator of Apoptosis and Autophagy. Molecules 22:1–18.

    CAS  Article  Google Scholar 

  8. 8.

    Clausen MV, Hilbers F, Poulsen H (2017) The structure and function of the Na, K-ATPase isoforms in health and disease. Front Physiol 8:1–16.

    Article  Google Scholar 

  9. 9.

    Mijatovic T, Dufrasne F, Kiss R (2012) Cardiotonic Steroids-Mediated Targeting of the Na+/K+-ATPase to Combat Chemoresistant Cancers. Curr Med Chem 19:627–646

    CAS  Article  Google Scholar 

  10. 10.

    Amarelle L, Lecuona E (2018) The Antiviral Effects of Na, K-ATPase Inhibition: A Minireview. Int J Mol Sci 19:2154.

    CAS  Article  PubMed Central  Google Scholar 

  11. 11.

    Diederich M, Muller F, Cerella C (2016) Cardiac glycosides : From molecular targets to immunogenic cell death. Biochem Pharmacol.

    Article  PubMed  Google Scholar 

  12. 12.

    Schneider N, Cerella C, Simões CMO, Diederich M (2017) Anticancer and Immunogenic Properties of Cardiac Glycosides. Molecules 22:1–16.

    CAS  Article  Google Scholar 

  13. 13.

    Mijatovic T, Kiss R (2013) Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways. Planta Med 79:189–198.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Weigand KM, Laursen M, Swarts HGP et al (2014) Na+, K+-ATPase isoform selectivity for digitalis-like compounds is determined by two amino acids in the first extracellular loop. Chem Res Toxicol 27:2082–2092.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Schneider N, Silva I, Persich L et al (2017) Cytotoxic effects of the cardenolide convallatoxin and its Na. Mol Cell Biochem, K-ATPase regulation.

    Google Scholar 

  16. 16.

    Dimas K, Papadopoulou N, Baskakis C et al (2016) Steroidal Cardiac Na +/K+ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in Vitro and in Prostate and Lung Cancer Xenografts in Vivo. Anticancer Agents Med Chem 14:1–9.

    CAS  Article  Google Scholar 

  17. 17.

    Mazumder A, Cerella C, Diederich M (2018) Natural scaffolds in anticancer therapy and precision medicine. Biotechnol Adv 36:1563–1585.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Litan A, Langhans SA (2015) Cancer as a channelopathy: ion channels and pumps in tumor development and progression. Front Cell Neurosci 9:86.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Lastraioli E, Iorio J, Arcangeli A (2014) Ion channel expression as promising cancer biomarker. Biochim Biophys Acta 8571922:2685–2702.

    CAS  Article  Google Scholar 

  20. 20.

    Eren OO, Ozturk MA, Sonmez OU, Oyan B (2015) Voltage-gated sodium channel blockers can augment the efficacy of chemotherapeutics by their inhibitory effect on epithelial-mesenchymal transition. Med Hypotheses 84:11–13.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Peretti M, Angelini M, Savalli N et al (2015) Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets. Biochim Biophys Acta 1848:2523–2531.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Black JA, Waxman SG (2013) Noncanonical Roles of Voltage-Gated Sodium Channels. Neuron 80:280–291.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Roger S, Potier M, Vandier C et al (2006) Voltage-gated sodium channels : new targets in cancer therapy ? Curr Pharm Des 80:280–291.

    Article  Google Scholar 

  24. 24.

    Rao SG, Ponnalagu D, Patel NJ, Singh H (2018) Three Decades of Chloride Intracellular Channel Proteins: from organelle to organ physiology. Curr Protoc Pharmacol 80:1–22.

    CAS  Article  Google Scholar 

  25. 25.

    Okada Y, Shimizu T, Maeno E et al (2006) Volume-sensitive Chloride Channels Involved in Apoptotic Volume Decrease and Cell Death. J Membrane Biol.

    Article  Google Scholar 

  26. 26.

    Fujii T, Shimizu T, Yamamoto S et al (2018) BBA - Molecular Basis of Disease Crosstalk between Na +, K + -ATPase and a volume-regulated anion channel in membrane microdomains of human cancer cells. BBA - Mol Basis Dis 1864:3792–3804.

    CAS  Article  Google Scholar 

  27. 27.

    Schneider N, Cerella C, Lee JY et al (2018) Cardiac glycoside glucoevatromonoside induces cancer type-specific cell death. Front Pharmacol.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Braga F, Kreis W, Braga De Oliveira A (1996) Isolation of cardenolides from a Brazilian cultivar of Digitalis lanata by rotation locular counter-current chromatography. J Chromatogr A 756:287–291.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Mao W, Zhang J, Körner H et al (2019) The Emerging Role of Voltage-Gated Sodium Channels in Tumor Biology 9:1–8.

    Article  Google Scholar 

  30. 30.

    Campbell TM, Main MJ, Fitzgerald EM (2013) Functional expression of the voltage-gated Na+-channel Nav1.7 is necessary for EGF-mediated invasion in human non-small cell lung cancer cells. J Cell Sci 126:4939–4949.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1:1112–1116.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Lines C, Krueger S (2011) Cancer Cell Culture. Methods 731:359–370.

    Article  Google Scholar 

  33. 33.

    Henry CM, Hollville E, Martin SJ (2013) Measuring apoptosis by microscopy and flow cytometry. Methods 61:90–97.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Liang C-C, Park AY, Guan J-L (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2:329–333.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Hulkower KI, Herber RL (2011) Cell Migration and Invasion Assays as Tools for Drug Discovery. Pharmaceutics 3:107–124.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Franken N, a P, Rodermond HM, Stap J, et al (2006) Clonogenic assay of cells in vitro. Nat Protoc 1:2315–2319.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Friedrich J, Seidel C, Ebner R, Kunz-Schughart L (2009) Spheroid-based drug screen: considerations and practical approach. Nat Protoc 4:309–324.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Jorgensen P (1974) Purification and characterization of (Na+ plus K+ )-ATPase. 3. Purification from the outer medulla of mammalian kidney after selective removal of membrane components by sodium dodecylsulphate. Biochim Biophys Acta 12:36–52

    Article  Google Scholar 

  39. 39.

    Jensen BYJ, Nrby JG, Ottolenghi P (1984) Binding of sodium and potassium to the sodium pump of pig kidney evaluated from nucleotide-binding behaviour. J Physiol 346:219–241

    CAS  Article  Google Scholar 

  40. 40.

    Sousa L, Garcia IJP, Costa TGF et al (2015) Effects of Iron Overload on the Activity of Na, K-ATPase and Lipid Profile of the Human Erythrocyte Membrane. PLoS ONE 10:e0132852.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Fiske C, Subbarow Y (1925) The Colorimetric determination of Phosphorus. J Biol Chem 66:375–400.

    CAS  Article  Google Scholar 

  42. 42.

    Noël F, Pimenta PHC, Dos Santos AR et al (2011) Δ2,3 -Ivermectin ethyl secoester, a conjugated ivermectin derivative with leishmanicidal activity but without inhibitory effect on mammalian P-type ATPases. Naunyn Schmiedebergs Arch Pharmacol 383:101–107.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Fontes CFL, Scofano HM, Barrabin H, Norby JG (1995) The effect of dilmethylsulfoxide on the substrate site of Na + / K + -ATPase studied through phosphorylation by inorganic phosphate and ouabain binding. Biochim Biophys Acta 1235:43–51.

    Article  PubMed  Google Scholar 

  44. 44.

    Chou T (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70:440–446.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Chou T (2006) Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies □. Pharmacol Rev 58:621–681.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Silva FKB, Villodre ES et al (2016) A guide for the analysis of long-term population growth in cancer. Tumor Biol 37:13743–13749.

    Article  Google Scholar 

  47. 47.

    Gomes ER, Novais MV, Silva IT et al (2018) Long-circulating and fusogenic liposomes loaded with a glucoevatromonoside derivative induce potent antitumor response. Biomed Pharmacother 108:1152–1161.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Elbaz H, Stueckle TA, Wang HYL et al (2012) Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells. Toxicol Appl Pharmacol 258:51–60.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Wang Y, Qiu Q, Shen J-J et al (2012) Cardiac glycosides induce autophagy in human non-small cell lung cancer cells through regulation of dual signaling pathways. Int J Dev Biol 44:1813–1824.

    CAS  Article  Google Scholar 

  50. 50.

    Leu WJ, Chang HS, Chan SH et al (2014) Reevesioside A, a cardenolide glycoside, induces anticancer activity against human hormone-refractory prostate cancers through suppression of c-myc expression and induction of G1 arrest of the cell cycle. PLoS ONE 9:1–13.

    CAS  Article  Google Scholar 

  51. 51.

    Feng B, Guo Y-W, Huang C-G et al (2010) 2’-epi-2’-O-Acetylthevetin B extracted from seeds of Cerbera manghas L. induces cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Chem Biol Interact 183:142–153.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Xu Z-W, Wang F-M, Gao M-J et al (2011) Cardiotonic steroids attenuate ERK phosphorylation and generate cell cycle arrest to block human hepatoma cell growth. J Steroid Biochem Mol Biol 125:181–191.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Ferlay J, Shin HR, Bray F et al (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917.

    CAS  Article  Google Scholar 

  54. 54.

    Perlikos F, Harrington KJ, Syrigos KN (2013) Key molecular mechanisms in lung cancer invasion and metastasis: A comprehensive review. Crit Rev Oncol Hematol 87:1–11.

    Article  PubMed  Google Scholar 

  55. 55.

    Pongrakhananon V, Chunhacha P, Chanvorachote P (2013) Ouabain Suppresses the Migratory Behavior of Lung Cancer Cells. PLoS ONE.

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Bagrov AY, Shapiro JI, Fedorova OV (2009) Endogenous Cardiotonic Steroids : Physiology, Pharmacology, and Novel Therapeutic Targets. Pharmacol Rev 61:9–38.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Schneider N, Geller FC, Persich L et al (2016) Inhibition of cell proliferaiton, invasion and migration by the cardenolides digitoxigenin monodigitoxoside and convallatoxin in human lung cancer cell line. Nat Prod Res 30:1327–1331.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    (2018) AMERICAN CANCER SOCIETY. In: Cancer.

  59. 59.

    Schneider N, Persich L, Rocha SC et al (2018) Cytotoxic and cytostatic effects of digitoxigenin monodigitoxoside (DGX) in human lung cancer cells and its link to Na, K-ATPase. Biomed Pharmacother 97:684–696.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Bertol JW, Rigotto C, de Pádua RM et al (2011) Antiherpes activity of glucoevatromonoside, a cardenolide isolated from a Brazilian cultivar of Digitalis lanata. Antiviral Res 92:73–80.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Munkert J, Santiago Franco M, Nolte E et al (2017) Production of the Cytotoxic Cardenolide Glucoevatromonoside by Semisynthesis and Biotransformation of Evatromonoside by a Digitalis lanata Cell Culture. Planta Med 83:1035–1043.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Laursen M, Lindholt J, Yatime L et al (2014) Structures and characterization of digoxin- and bufalin-bound Na +, K + -ATPase compared with the ouabain-bound complex. Proc Natl Acad Sci USA.

    Article  PubMed  Google Scholar 

  63. 63.

    Yatime L, Laursen M, Morth JP et al (2011) Structural insights into the high affinity binding of cardiotonic steroids to the Na +, K + -ATPase. J Struct Biol 174:296–306.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Arystarkhova E (2016) Beneficial Renal and Pancreatic Phenotypes in a Mouse Deficient in FXYD2 Regulatory Subunit of. Physiol, Front.

    Google Scholar 

  65. 65.

    Zhang J, Xu C, Gao Y et al (2020) A Novel Long Non-coding RNA, Resistance by Sponging the miR-432–5p in Non-small Cell Lung Cancer Cells. Oncol, Front.

    Google Scholar 

  66. 66.

    Thul PJ, Thul PJ, Åkesson L et al (2017) A subcellular map of the human proteome. Science 80(3321):1–21.

    CAS  Article  Google Scholar 

  67. 67.

    Hoffman JF, Wickrema A, Potapova O et al (2002) Na pump isoforms in human erythroid progenitor cells and mature erythrocytes. PNAS 99:14572–14577.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Hsu I, Chou C, Wu Y et al (2016) Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma. Oncotarget 7:62925–62938.

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Wang HL, Wang HL, Doherty GAO (2012). Modulators of Na / K-ATPase : a patent review Modulators of Na / K-ATPase : a patent review.

    Article  Google Scholar 

  70. 70.

    Bechmann MB, Rotoli D, Morales M, Martín-vasallo P (2016) Na, K-ATPase Isozymes in Colorectal Cancer and Liver Metastases. Front Physiol 7:1–11.

    Article  Google Scholar 

  71. 71.

    Cherniavsky Lev M, Karlish SJD, Garty H (2015) Cardiac glycosides induced toxicity in human cells expressing α1-, α2-, or α3-isoforms of Na-K-ATPase. Am J Physiol - Cell Physiol 309:C126–C135.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Mijatovic T, Van Quaquebeke E, Delest B et al (2007) Cardiotonic steroids on the road to anti-cancer therapy. Biochim Biophys Acta 1776:32–57.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Magpusao AN, Omolloh G, Johnson J et al (2015) Cardiac Glycoside Activities Link Na+/K+ATPase Ion-Transport to Breast Cancer Cell Migration via Correlative SAR. ACS Chem Biol 10:561–569.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Fuerstenwerth H (2014) On the differences between ouabain and digitalis glycosides. Am J Ther 21:35–42.

    Article  PubMed  Google Scholar 

  75. 75.

    Xie C-M, Liu X-Y, Yu S, Cheng CHK (2013) Cardiac glycosides block cancer growth through HIF-1α- and NF-κB-mediated Plk1. Carcinogenesis 34:1870–1880.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Askari A (2019) The sodium pump and digitalis drugs : Dogmas and fallacies. Pharmacol Res Perspect.

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Takara K, Takagi K, Tsujimoto M et al (2003) Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneously down-regulates steroid xenobiotic receptor mRNA. Biochem Biophys Res Commun 306:116–120.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Fujii T, Shimizu T, Takeshima H, Sakai H (2019) Cancer Cell-Specific Functional Relation Between Na +, K +-ATPase and Volume-Regulated Anion Channel. Nihon Yakurigaku Zasshi 154:103–107.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Menegaz D, Mizwicki MT, Barrientos-duran A et al (2011) Vitamin D Receptor VDR Regulation of Voltage- Gated Chloride Channels by Ligands Preferring. Mol Endocrinol 25:1289–1300.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Menegaz D, Barrientos-duran A, Kline A et al (2010) 1,25(OH)2 -Vitamin D3 stimulation of secretion via chloride channel activation in Sertoli cells. J Steroid Biochem Mol Biol 119:127–134.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Khajah MA, Mathew PM, Luqmani YA (2018) Na + / K + ATPase activity promotes invasion of endocrine resistant breast cancer cells. PLoS ONE 13:1–27

    Article  Google Scholar 

  82. 82.

    Leanza L, Biasutto L, Managò A et al (2013) Intracellular ion channels and cancer. Front Physiol 4:1–7.

    Article  Google Scholar 

  83. 83.

    Jentsch TJ, Stein V, Weinreich F, Zdebik AA (2002) Molecular Structure and Physiological Function of Chloride Channels. Physiol Rev 82:503–568.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Prevarskaya N, Skryma R, Shuba Y (2010) Ion channels and the hallmarks of cancer. Trends Mol Med 16:107–121.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Munden RF, Godoy MCB (2013) Lung cancer screening: State of the art. J Surg Oncol 108:270–274.

    Article  PubMed  Google Scholar 

  86. 86.

    Silva I, Munkert J, Nolte E et al (2018) Cytotoxicity of AMANTADIG – a semisynthetic digitoxigenin derivative – alone and in combination with docetaxel in human hormone-refractory prostate cancer cells and its effect on Na+/K+-ATPase inhibition. Biomed Pharmacother 107:464–474.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Shraibom N (2013) Cardiac glycoside analogs in combination with emodin for cancer therapy

  88. 88.

    Felth J, Rickardson L, Rosén J et al (2009) Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs. J Nat Prod 72:1969–1974.

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Yakisich JS, Azad N, Venkatadri R et al (2016) Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel. Oncol Rep 35:878–886.

    CAS  Article  PubMed  Google Scholar 

Download references


The authors acknowledge the Brazilian funding agencies FINEP/MCTI (CT-INFRA 150-2009/NUBIOCEL) and CNPq/MCTI (Grants 305878/2016-6 of CMOS; 472544/2013-6 and 490057/2011-0 of FCB) as well as Marie Curie Foundation/European Community (FP7 IRSES, grant 295251 of WK). They are also grateful to CNPq/MCTI and CAPES/MEC for the post-doctoral fellowships of NFZS (CNPq/PDJ 150303/2016-5 and CAPES/PNPD 23080.000686/2017-48 from PPG Pharmacy/UFSC) and DM (CAPES/BJT 400109/2014-0 from PPG Biochemistry/UFSC) and for the research fellowships of LP, FCB, FRMBS, and CMOS. Special thanks go to the Brazilian National Cancer Institute José Alencar Gomes da Silva (INCA, Rio de Janeiro, RJ) for the donation of H460 cell line.

Author information



Corresponding author

Correspondence to Cláudia Maria Oliveira Simões.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schneider, N.F.Z., Menegaz, D., Dagostin, A.L.A. et al. Cytotoxicity of glucoevatromonoside alone and in combination with chemotherapy drugs and their effects on Na+,K+-ATPase and ion channels on lung cancer cells. Mol Cell Biochem (2021).

Download citation


  • Cardiac glycosides
  • Glucoevatromonoside
  • Lung cancer cells
  • Ion channels
  • Synergism