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01-08-2013 | REVIEW

Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials

Authors: M. Slingerland, C. Cerella, H. J. Guchelaar, M. Diederich, H. Gelderblom

Published in: Investigational New Drugs | Issue 4/2013

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.

Bessen HA (1986) Therapeutic and toxic effects of digitalis: William Withering, 1785. J Emerg Med 4(3):243–248PubMedCrossRef

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):32–57PubMed

Newman RA, Yang P, Pawlus AD, Block KI (2008) Cardiac glycosides as novel cancer therapeutic agents. Mol Interv 8(1):36–49PubMedCrossRef

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 2:49–54PubMed

Stenkvist B, Bengtsson E, Eriksson O, Holmquist J, Nordin B, Westman-Naeser S (1979) Cardiac glycosides and breast cancer. Lancet 1:563PubMedCrossRef

Stenkvist B, Pengtsson E, Dahlqvist B, Eriksson O, Jarkrans T, Nordin B (1982) Cardiac glycosides and breast cancer, revisited. N Engl J Med 306:484PubMed

Scheiner-Bobis G (2002) The sodium pump: its molecular properties and mechanics of ion transport. Eur J Biochem 269:2424–2433PubMedCrossRef

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):363–386PubMedCrossRef

10.

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):313–318PubMedCrossRef

11.

Yu SP (2003) Na(+), K(+)-ATPase: the new face of an old player in pathogenesis and apoptotic/hybrid cell death. Biochem Pharmacol 66(8):1601–1609PubMedCrossRef

12.

Bortner CD, Cidlowski JA (2002) Apoptotic volume decrease and the incredible shrinking cell. Cell Death Differ 9(12):1307–1310PubMedCrossRef

13.

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):39176–39184PubMedCrossRef

14.

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):205–215CrossRef

15.

Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4(7):552–565PubMedCrossRef

16.

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):3807–3812PubMed

17.

Cerella C, Dicato M, Diederich M (2013) Assembling the puzzle of anti-cancer mechanisms triggered by cardiac glycosides. Mitochondrion 13:225–234PubMedCrossRef

18.

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):786–795PubMedCrossRef

19.

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):1–33PubMedCrossRef

20.

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):1–24PubMed

21.

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):2766–2770PubMedCrossRef

22.

Perona R, Serrano R (1988) Increased pH and tumorigenicity of fibroblasts expressing a yeast proton pump. Nature 334(6181):438–440PubMedCrossRef

23.

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):2185–2197PubMedCrossRef

24.

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):1427–1434PubMed

25.

López-Lázaro M (2006) HIF-1: hypoxia-inducible factor or dysoxia-inducible factor? FASEB J 20(7):828–832PubMedCrossRef

26.

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):2801–2808PubMed

27.

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):514–521PubMedCrossRef

28.

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):752–758PubMedCrossRef

29.

Lagadic-Gossmann D, Huc L, Lecureur V (2004) Alterations of intracellular pH homeostasis in apoptosis: origins and roles. Cell Death Differ 11(9):953–961PubMedCrossRef

30.

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):654–658PubMedCrossRef

31.

Matsuyama S, Reed JC (2000) Mitochondria-dependent apoptosis and cellular pH regulation. Cell Death Differ 7(12):1155–1165PubMedCrossRef

32.

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):318–325PubMedCrossRef

33.

Xie K (2001) Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev 12(4):375–391PubMedCrossRef

34.

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):4521–4526PubMed

35.

Yuan A, Chen JJ, Yao PL, Yang PC (2005) The role of interleukin-8 in cancer cells and microenvironment interaction. Front Biosci 10:853–865PubMedCrossRef

36.

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):13–23PubMedCrossRef

37.

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):7693–7698PubMedCrossRef

38.

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):9631–9636PubMedCrossRef

39.

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):1642–1645PubMedCrossRef

40.

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):895–898PubMedCrossRef

41.

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):1493–1497PubMedCrossRef

42.

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):875–883PubMedCrossRef

43.

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):10585–10593PubMedCrossRef

44.

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):19709–19719PubMedCrossRef

45.

Kometiani P, Liu L, Askari A (2005) Digitalis-induced signaling by Na+/K + -ATPase in human breast cancer cells. Mol Pharmacol 67(3):929–936PubMedCrossRef

46.

Bagrov AY, Shapiro JI, Fedorova OV (2009) Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev 61(1):9–38PubMedCrossRef

47.

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):152–158CrossRef

48.

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):744–755PubMedCrossRef

49.

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):1386–1393PubMedCrossRef

50.

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–F990CrossRef

51.

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–C481PubMedCrossRef

52.

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 78:1–10PubMedCrossRef

53.

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 21:637–643PubMed

54.

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 125:181–191PubMedCrossRef

55.

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 183:142–153PubMedCrossRef

56.

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 14:1193–1198PubMed

57.

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 51:1365–1375PubMedCrossRef

58.

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 82:735–741PubMedCrossRef

59.

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):143ra99PubMedCrossRef

60.

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):1573–1577PubMedCrossRef

61.

Goldin AG, Safa AR (1984) Digitalis and cancer. Lancet 1(8386):1134PubMedCrossRef

62.

Haux J, Klepp O, Spigset O, Tretli S (2001) Digitoxin medication and cancer; case control and internal dose–response studies. BMC Cancer 1:11PubMedCrossRef

63.

Friedman GD (1984) Digitalis and breastcancer. Lancet 2(8407):875PubMedCrossRef

64.

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):R102PubMedCrossRef

65.

Shiratori O (1967) Growth inhibitory effect of cardiac glycosides and aglycones on neoplastic cells: in vitro and in vivo studies. Gann 58(6):521–528PubMed

66.

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 60:3838–3847PubMed

67.

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):469–472PubMedCrossRef

68.

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):423–427CrossRef

69.

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)

70.

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 48:849–856PubMedCrossRef

71.

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):402–412PubMedCrossRef

72.

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):391–399PubMedCrossRef

73.

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):1285–1296PubMedCrossRef

74.

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 62:211–222PubMedCrossRef

75.

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 68:164–173CrossRef

76.

Lefranc F, Kiss R (2008) The sodium pump alpha-1 subunit as a potential target to combat apoptosis-resistant glioblastomas. Neoplasia 10(3):198–206PubMed

77.

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 23:2411–2422PubMedCrossRef

78.

López-Lázaro M (2007) Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved. Expert Opin Ther Targets 11(8):1043–1053PubMedCrossRef

Title: Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials
Authors: M. Slingerland
C. Cerella
H. J. Guchelaar
M. Diederich
H. Gelderblom
Publication date: 01-08-2013
Publisher: Springer US
Published in: Investigational New Drugs / Issue 4/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-013-9984-1

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