Summary
Cardiac glycosides have a long history in the treatment of cardiac disease. However, several preclinical studies as well as two phase I studies have shown that cardenolides may also possess anticancer effects. The mechanisms of these anticancer effects may include intracellular decrease of K+ and increase of Na+ and Ca2+; intracellular acidification; inhibition of IL-8 production and of the TNF-α/NF-κB pathway; inhibition of DNA topoisomerase II and activation of the Src kinase pathway. To date three cardiac glycosides have been developed for treatment of cancer and were tested in a phase 1 clinical trial to determine dose limiting toxicities and maximum tolerated dose. Future studies of this novel class of anticancer drugs are warranted to determine their possible role in cancer treatment.
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References
Bessen HA (1986) Therapeutic and toxic effects of digitalis: William Withering, 1785. J Emerg Med 4(3):243–248
Mijatovic T, Van Quaquebeke E, Delest B, Debeir O, Darro F, Kiss R (2007) Cardiotonic steroids on the road to anti-cancer therapy. Biochim Biophys Acta 1776(1):32–57
Newman RA, Yang P, Pawlus AD, Block KI (2008) Cardiac glycosides as novel cancer therapeutic agents. Mol Interv 8(1):36–49
Stenkvist B, Bengtsson E, Eklund G et al (1980) Evidence of a modifying influence of heart glucosides on the development of breast cancer. Anal Quant Cytol 2:49–54
Stenkvist B, Bengtsson E, Eriksson O, Holmquist J, Nordin B, Westman-Naeser S (1979) Cardiac glycosides and breast cancer. Lancet 1:563
Stenkvist B, Pengtsson E, Dahlqvist B, Eriksson O, Jarkrans T, Nordin B (1982) Cardiac glycosides and breast cancer, revisited. N Engl J Med 306:484
Scheiner-Bobis G (2002) The sodium pump: its molecular properties and mechanics of ion transport. Eur J Biochem 269:2424–2433
Boron WF, Boulpaep EL (2004) Medical physiology. Elsevier, Philadelphia
Yu SP (2003) Regulation and critical role of potassium homeostasis in apoptosis. Prog Neurobiol 70(4):363–386
Bortner CD, Cidlowski JA (2004) The role of apoptotic volume decrease and ionic homeostasis in the activation and repression of apoptosis. Pflugers Arch 448(3):313–318
Yu SP (2003) Na(+), K(+)-ATPase: the new face of an old player in pathogenesis and apoptotic/hybrid cell death. Biochem Pharmacol 66(8):1601–1609
Bortner CD, Cidlowski JA (2002) Apoptotic volume decrease and the incredible shrinking cell. Cell Death Differ 9(12):1307–1310
Bortner CD, Cidlowski JA (2003) Uncoupling cell shrinkage from apoptosis reveals that Na + influx is required for volume loss during programmed cell death. J Biol Chem 278(40):39176–39184
Panayiotidis MI, Bortner CD, Cidlowski JA (2006) On the mechanism of ionic regulation of apoptosis: would the Na+/K + -ATPase please stand up? Acta Physiol (Oxf) 187(1–2):205–215
Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4(7):552–565
McConkey DJ, Lin Y, Nutt LK, Ozel HZ, Newman RA (2000) Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res 60(14):3807–3812
Cerella C, Dicato M, Diederich M (2013) Assembling the puzzle of anti-cancer mechanisms triggered by cardiac glycosides. Mitochondrion 13:225–234
Cardone RA, Casavola V, Reshkin SJ (2005) The role of disturbed pH dynamics and the Na+/H + exchanger in metastasis. Nat Rev Cancer 5(10):786–795
Harguindey S, Pedraz JL, García Cañero R, Pérez de Diego J, Cragoe EJ (1995) Hydrogen ion-dependent oncogenesis and parallel new avenues to cancer prevention and treatment using a H(+)-mediated unifying approach: pH-related and pH-unrelated mechanisms. Crit Rev Oncog 6(1):1–33
Harguindey S, Orive G, Luis Pedraz J, Paradiso A, Reshkin SJ (2005) The role of pH dynamics and the Na+/H + antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin–one single nature. Biochim Biophys Acta 1756(1):1–24
Ober SS, Pardee AB (1987) Intracellular pH is increased after transformation of Chinese hamster embryo fibroblasts. Proc Natl Acad Sci U S A 84(9):2766–2770
Perona R, Serrano R (1988) Increased pH and tumorigenicity of fibroblasts expressing a yeast proton pump. Nature 334(6181):438–440
Reshkin SJ, Bellizzi A, Caldeira S, Albarani V, Malanchi I, Poignee M, Alunni-Fabbroni M, Casavola V, Tommasino M (2000) Na+/H + exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J 14(14):2185–2197
Rich IN, Worthington-White D, Garden OA, Musk P (2000) Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na(+)/H(+) exchanger. Blood 95(4):1427–1434
López-Lázaro M (2006) HIF-1: hypoxia-inducible factor or dysoxia-inducible factor? FASEB J 20(7):828–832
Zanke BW, Lee C, Arab S, Tannock IF (1998) Death of tumor cells after intracellular acidification is dependent on stress-activated protein kinases (SAPK/JNK) pathway activation and cannot be inhibited by Bcl-2 expression or interleukin 1beta-converting enzyme inhibition. Cancer Res 58(13):2801–2808
Hirpara JL, Clément MV, Pervaiz S (2001) Intracellular acidification triggered by mitochondrial-derived hydrogen peroxide is an effector mechanism for drug-induced apoptosis in tumor cells. J Biol Chem 276(1):514–521
Cho YL, Lee KS, Lee SJ, Namkoong S, Kim YM, Lee H, Ha KS, Han JA, Kwon YG, Kim YM (2005) Amiloride potentiates TRAIL-induced tumor cell apoptosis by intracellular acidification-dependent Akt inactivation. Biochem Biophys Res Commun 326(4):752–758
Lagadic-Gossmann D, Huc L, Lecureur V (2004) Alterations of intracellular pH homeostasis in apoptosis: origins and roles. Cell Death Differ 11(9):953–961
Gottlieb RA, Nordberg J, Skowronski E, Babior BM (1996) Apoptosis induced in Jurkat cells by several agents is preceded by intracellular acidification. Proc Natl Acad Sci U S A 93(2):654–658
Matsuyama S, Reed JC (2000) Mitochondria-dependent apoptosis and cellular pH regulation. Cell Death Differ 7(12):1155–1165
Matsuyama S, Llopis J, Deveraux QL, Tsien RY, Reed JC (2000) Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nat Cell Biol 2(6):318–325
Xie K (2001) Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev 12(4):375–391
Abdollahi T, Robertson NM, Abdollahi A, Litwack G (2003) Identification of interleukin 8 as an inhibitor of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in the ovarian carcinoma cell line OVCAR3. Cancer Res 63(15):4521–4526
Yuan A, Chen JJ, Yao PL, Yang PC (2005) The role of interleukin-8 in cancer cells and microenvironment interaction. Front Biosci 10:853–865
Juncker T, Cerella C, Teiten MH, Morceau F, Schumacher M, Ghelfi J, Gaascht F, Schnekenburger M, Henry E, Dicato M, Diederich M (2011) UNBS1450, a steroid cardiac glycoside inducing apoptotic cell death in human leukemia cells. Biochem Pharmacol 81(1):13–23
Srivastava M, Eidelman O, Zhang J, Paweletz C, Caohuy H, Yang Q, Jacobson KA, Heldman E, Huang W, Jozwik C, Pollard BS, Pollard HB (2004) Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. Proc Natl Acad Sci U S A 101(20):7693–7698
Yang Q, Huang W, Jozwik C, Lin Y, Glasman M, Caohuy H, Srivastava M, Esposito D, Gillette W, Hartley J, Pollard HB (2005) Cardiac glycosides inhibit TNF-alpha/NF-kappaB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor. Proc Natl Acad Sci U S A 102(27):9631–9636
López-Lázaro M, Pastor N, Azrak SS, Ayuso MJ, Austin CA, Cortés F (2005) Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients. J Nat Prod 68(11):1642–1645
López-Lázaro M, Pastor N, Azrak SS, Ayuso MJ, Cortés F, Austin CA (2006) Digitoxin, at concentrations commonly found in the plasma of cardiac patients, antagonizes etoposide and idarubicin activity in K562 leukemia cells. Leuk Res 30(7):895–898
Bielawski K, Winnicka K, Bielawska A (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(7):1493–1497
Hashimoto S, Jing Y, Kawazoe N, Masuda Y, Nakajo S, Yoshida T, Kuroiwa Y, Nakaya K (1997) Bufalin reduces the level of topoisomerase II in human leukemia cells and affects the cytotoxicity of anticancer drugs. Leuk Res 21(9):875–883
Liang M, Tian J, Liu L, Pierre S, Liu J, Shapiro J, Xie ZJ (2007) Identification of a pool of non-pumping Na/K-ATPase. J Biol Chem 282(14):10585–10593
Liang M, Cai T, Tian J, Qu W, Xie ZJ (2006) Functional characterization of Src-interacting Na/K-ATPase using RNA interference assay. J Biol Chem 281(28):19709–19719
Kometiani P, Liu L, Askari A (2005) Digitalis-induced signaling by Na+/K + -ATPase in human breast cancer cells. Mol Pharmacol 67(3):929–936
Bagrov AY, Shapiro JI, Fedorova OV (2009) Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev 61(1):9–38
Apel A, Rachel P, Cohen O, Mayan H (2013) Digoxin-associated decrease in parathyroid hormone (PTH) concentrations in patients with atrial fibrillation. Eur J Clin Investig 43(2):152–158
Bignami E, Casamassima N, Frati E, Lanzani C, Corno L, Alfieri O, Gottlieb S, Simonini M, Shah KB, Mizzi A, Messaggio E, Zangrillo A, Ferrandi M, Ferrari P, Bianchi G, Hamlyn JM, Manunta P (2013) Preoperative endogenous ouabain predicts acute kidney injury in cardiac surgery patients. Crit Care Med 41(3):744–755
Nesher M, Bai Y, Li D, Rosen H, Lichtstein D, Liu L (2012) Interaction of atrial natriuretic peptide and ouabain in the myocardium. Can J Physiol Pharmacol 90(10):1386–1393
Jansson K, Nguyen AN, Magenheimer BS, Reif GA, Aramadhaka LR, Bello-Reuss E, Wallace DP, Calvet JP, Blanco G (2012) Endogenous concentrations of ouabain act as a cofactor to stimulate fluid secretion and cyst growth of in vitro ADPKD models via cAMP and EGFR-Src-MEK pathways. Am J Physiol Ren Physiol 303(7):F982–F990
Cereijido M, Contreras RG, Shoshani L, Larre I (2012) The Na + -K + -ATPase as self-adhesion molecule and hormone receptor. Am J Physiol Cell Physiol 302(3):C473–C481
Juncker T, Schumacher M, Dicato M, Diederich M (2009) UNBS1450 from Calotropis procera as a regulator of signaling pathways involved in proliferation and cell death. Biochem Pharmacol 78:1–10
Takai N, Ueda T, Nishida M, Nasu K, Narahara H (2008) Bufalin induces growth inhibition, cell cycle arrest and apoptosis in human endometrial and ovarian cancer cells. Int J Mol Med 21:637–643
Xu ZW, Wang FM, Gao MJ, Chen XY, Shan NN, Cheng SX, Mai X, Zala GH, Hu WL, Xu RC (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
Feng B, Guo YW, Huang CG, Li L, Chen RH, Jiao BH (2010) 2′-epi-2′-OAcetylthevetin 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
Jing Y, Watabe M, Hashimoto S, Nakajo S, Nakaya K (1994) Cell cycle arrest and protein kinase modulating effect of bufalin on human leukemia ML1 cells. Anticancer Res 14:1193–1198
Xie CM, Chan WY, Yu S, Zhao J, Cheng CH (2011) Bufalin induces autophagymediated cell death in human colon cancer cells through reactive oxygen species generation and JNK activation. Free Radic Biol Med 51:1365–1375
Zhao Q, Guo Y, Feng B, Li L, Huang C, Jiao B (2011) Neriifolin from seeds of Cerbera manghas L. induces cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Fitoterapia 82:735–741
Menger L, Vacchelli E, Adjemian S, Martins I, Ma Y, Shen S, Yamazaki T, Sukkurwala AQ, Michaud M, Mignot G, Schlemmer F, Sulpice E, Locher C, Gidrol X, Ghiringhelli F, Modjtahedi N, Galluzzi L, André F, Zitvogel L, Kepp O, Kroemer G (2012) Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci Transl Med 4(143):143ra99
Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, Shen S, Kepp O, Scoazec M, Mignot G, Rello-Varona S, Tailler M, Menger L, Vacchelli E, Galluzzi L, Ghiringhelli F, di Virgilio F, Zitvogel L, Kroemer G (2011) Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334(6062):1573–1577
Goldin AG, Safa AR (1984) Digitalis and cancer. Lancet 1(8386):1134
Haux J, Klepp O, Spigset O, Tretli S (2001) Digitoxin medication and cancer; case control and internal dose–response studies. BMC Cancer 1:11
Friedman GD (1984) Digitalis and breastcancer. Lancet 2(8407):875
Ahern TP, Lash TL, Sørensen HT, Pedersen L (2008) Digoxin treatment is associated with an increased incidence of breast cancer: a population-based case–control study. Breast Cancer Res 10(6):R102
Shiratori O (1967) Growth inhibitory effect of cardiac glycosides and aglycones on neoplastic cells: in vitro and in vivo studies. Gann 58(6):521–528
Manna SK, Sah NK, Newman R, Cismerps A, Aggarwal BB (2000) Oleandrin suppresses activation of nuclear transcription of factor-B, activator protein-2 and c-Jun NH2-terminal kinase. Cancer Res 60:3838–3847
Smith JA, Madden T, Vijjeswarapu M, Newman RA (2001) Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU 145 by Anvirzel and its cardiac glycoside component, oleandrin. Biochem Pharmacol 62(4):469–472
Mekhail T, Kaur H, Ganapathi R, Budd GT, Elson P, Bukowski RM (2006) Phase 1 trial of Anvirzel in patients with refractory solid tumors. Investig New Drugs 24(5):423–427
Henary HA, Kurzrock R, Falchook GS, Naing A, Moulder SL, Wheler JJ, Tsimberidou AM, Durand J, Yang P, Johansen MJ, Newman R, Khan R, Patel U, Hong DS (2011) Final results of a first-in-human phase I trial of PBI-05204, an inhibitor of AKT, FGF-2, NF-Kb, and p70S6K in advanced cancer patients. J Clin Oncol 29:(suppl; abstr 3023)
Van Quaquebeke E, Simon G, Andre A, Dewelle J, Yazidi ME, Bruyneel F, Tuti J, Nacoulma O, Guissou P, Decaestecker C, Braekman JC, Kiss R, Darro F (2005) Identification of a novel cardenolide (2″-oxovorusharin) from Calotropis procera and the hemisynthesis of novel derivatives displaying potent in vitro antitumor activities and high in vivo tolerance: structure-activity relationship analyses. J Med Chem 48:849–856
Mijatovic T, Mathieu V, Gaussin JF, De Nève N, Ribaucour F, Van Quaquebeke E, Dumont P, Darro F, Kiss R (2006) Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human nonsmall cell lung cancers. Neoplasia 8(5):402–412
Mijatovic T, Op De Beeck A, Van Quaquebeke E, Dewelle J, Darro F, de Launoit Y, Kiss R (2006) The cardenolide UNBS1450 is able to deactivate nuclear factor kappaBmediated cytoprotective effects in human non-small cell lung cancer cells. Mol Cancer Ther 5(2):391–399
Mijatovic T, De Neve N, Gailly P, Matthieu V, Haibe-Kains B, Bontempi G, Lapeira J, Decaestecker C, Facchini V, Kiss R (2008) Nucleolus and cMyc: potential targets of cardenolide-mediated anti-tumor activity. Mol Cancer Ther 7(5):1285–1296
Lefranc F, Mijatovic T, Kondo Y, Sauvage S, Roland I, Debeir O, Krstic D, Vasic V, Gailly P, Kondo S, Blanco G, Kiss R (2008) Targeting the alpha-1 subunit of the sodium pump to combat glioblastoma cells. Neurosurgery 62:211–222
Mijatovic T, Lefranc F, Van Quaquebeke E, Van Vynckt F, Darro F, Kiss R (2007) UNSB1450: a new hemi-synthetic cardenolide with promising anti-cancer activity. Drug Dev Res 68:164–173
Lefranc F, Kiss R (2008) The sodium pump alpha-1 subunit as a potential target to combat apoptosis-resistant glioblastomas. Neoplasia 10(3):198–206
Lefranc F, Brotchi J, Kiss R (2005) Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 23:2411–2422
López-Lázaro M (2007) Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved. Expert Opin Ther Targets 11(8):1043–1053
Acknowledgments
C. Cerella is supported by a “Waxweiler grant for cancer prevention research” from the Action LIONS “Vaincre le Cancer”. Research at LBMCC is financially supported by the Fondation de Recherche Cancer et Sang, the Recherches Scientifiques Luxembourg association, the Een Haerz fir kriibskrank Kanner association, the Action Lions Vaincre le Cancer association, the European Union (ITN “RedCat” 215009, interreg Iva project “Corena”) and the Télévie Luxembourg. Marc Diederich is supported by the National Research Foundation (NRF) by the MEST of Korea for Tumor Microenvironment Global Core Research Center (GCRC) grant, [grant number 2012-0001184]; by the Seoul National University Research grant and by the Research Settlement Fund for the new faculty of SNU.
Conflict of interest
C. Cerella is supported by a “Waxweiler grant for cancer prevention research” from the Action LIONS “Vaincre le Cancer”. Research at LBMCC is financially supported by the Fondation de Recherche Cancer et Sang, the Recherches Scientifiques Luxembourg association, the Een Haerz fir kriibskrank Kanner association, the Action Lions Vaincre le Cancer association, the European Union (ITN “RedCat” 215009, interreg Iva project “Corena”) and the Télévie Luxembourg. M. Diederich is supported by the National Research Foundation (NRF) by the MEST of Korea for Tumor Microenvironment Global Core Research Center (GCRC) grant, [grant number 2012-0001184]; by the Seoul National University Research grant and by the Research Settlement Fund for the new faculty of SNU.
The other authors declare that they have no conflict of interest.
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Slingerland, M., Cerella, C., Guchelaar, H.J. et al. Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials. Invest New Drugs 31, 1087–1094 (2013). https://doi.org/10.1007/s10637-013-9984-1
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DOI: https://doi.org/10.1007/s10637-013-9984-1