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Therapeutic Potential of Cardiac Glycosides Against Cancer

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Anticancer Plants: Natural Products and Biotechnological Implements

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Abstract

Cardiac glycosides represent a group of naturally derived compounds isolated from several plants and animal species. It is generally used in the treatment of cardiac congestion and various types of cardiac arrhythmias. The compounds of the cardiac glycoside group have been well characterised in inhibiting Na+/K+-ATPase pump and are responsible for the Na+, K+ and Ca2+ ion level exchange that resulted in the ionotropic activity that is useful for the treatment of various heart conditions. The therapeutic effect of cardiac glycosides as anticancer agents was revealed in the eighth century; however, the mechanisms of action by cardiac glycosides remain largely unknown. The aim of this chapter is to discuss the chemical structure, mechanisms of actions and other issues pertaining to the use of cardiac glycosides as potential anticancer agents.

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References

  • Barry W, Hasin Y, Smith T (1985) Sodium pump inhibition, enhanced calcium influx via sodium-calcium exchange, and positive inotropic response in cultured heart cells. Circ Res 56:231–241

    Article  CAS  PubMed  Google Scholar 

  • Braunwald E (1985) Effects of digitalis on the normal and the failing heart. J Am Coll Cardiol 5:A51–A59

    Article  Google Scholar 

  • Calderón-Montaño JM, Burgos-Morón E, Orta ML, Maldonado-Navas D, García-Domínguez I, López-Lázaro M (2014) Evaluating the cancer therapeutic potential of cardiac glycosides. Biomed Res Int 2014:794930. https://doi.org/10.1155/2014/794930

    Article  PubMed  PubMed Central  Google Scholar 

  • Chanvorachote P, Pongrakhananon V (2013) Ouabain down regulates Mcl-1 and sensitizes lung cancer cells to TRAIL-induced apoptosis. Am J Phys 304:263–272

    Article  CAS  Google Scholar 

  • Daut J (1983) Inhibition of the sodium pump in guinea-pig ventricular muscle by dihydro-ouabain: effects of external potassium and sodium. J Physiol 339:643–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De S, Banerjee S, Babu MN, Lakhmi MB, Babu TMS (2016) Review on cardiac glycosides in cancer research and cancer therapy. Indo Am J Pharma Res 6:5391–5400

    CAS  Google Scholar 

  • Elbaz HA, Stueckle TA, Tse W, Rojanasakul Y, Dinu CZ (2012) Digitoxin and its analogs as novel cancer therapeutics. Exp Hematol Oncol 1:1–10

    Article  CAS  Google Scholar 

  • Frese S, Frese-Schaper M, Andres AC, Miescher D, Zumkehr B, Schmid RA (2006) Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulating of death receptor 4 and 5. Cancer Res 66:5867–5874

    Article  CAS  PubMed  Google Scholar 

  • Gan N, Chen G, Zhang W, Zhou J (2012) Oleanen induces apoptosis of cervical cancer cells by up-regulation of Bim. Int J Gynecol Cancer 22:38–42

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Hauptman PJ, Kelly RA (1999) Digitalis. Circulation 99:1365–1270

    Article  Google Scholar 

  • Haux J, Klepp O, Spigset O, Tretli S (2001) Digitoxin medication and cancer; case control and internal dose-response studies. BioMed Cent 1:11–16

    CAS  Google Scholar 

  • Kang J, Lee M (2009) Overview of therapeutic drug monitoring. Korean. J Int Med 24:1–10

    Google Scholar 

  • Kaplan JH (2002) Biochemistry of Na+/K+-ATPase. Annu Rev Biochem 71:511–535

    Article  CAS  PubMed  Google Scholar 

  • Kokate CK, Purohit AP, Gokhale SB (2008) Drugs containing glycosides. In: Kokate CP (ed) Pharmacognosy. Nirali Prakashan, Pune

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • KÅ™en V, Martínková L (2001) Glycosides in medicine: the role of glycosidic residue in biological activity. Curr Med Chem 8:1303–1328

    Article  PubMed  Google Scholar 

  • Laphookhieo S, Cheenpracha S, Karalai C, Chantrapromma S, Rat-a-Pa Y, Ponglimanont C, Chantrapromma K (2004) Cytotoxic cardenolide glycoside from the seeds of Cerbera odollam. Phytochemistry 65:507–510

    Article  CAS  PubMed  Google Scholar 

  • López-Lázaro M (2007) Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved. Exp Opin Ther Targets 11:1043–4053

    Article  Google Scholar 

  • López-Lázaro M, Pastor N, Azrak SS, Ayuso MJ, Austin CA, Cortes F (2005) Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients. J Nat Prod 68:1642–1645

    Article  CAS  PubMed  Google Scholar 

  • López-Lázaro M, Pastor N, Azrak SS, Ayuso MJ, Cortes F, Austin CA (2006) Digitoxin, at concentrations commonly found in the plasma of cardiac patients, antagonizes etoposide and idarubicin activity in K562 leukemia cells. Leukemia Res 30:895–898

    Article  CAS  Google Scholar 

  • Mijatovic T, Mathieu V, Gaussin J, Néve ND, Ribaucour F, Quaquebeke EV, Dumont P, Darro F, Kiss R (2006) Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers. Neoplasia 8:402–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mijatovic T, Quaquebeke EV, Delest B, Debeir O, Darro F, Kiss R (2007) Cardiotonic steroids on the road to anti-cancer therapy. Biochim Biophys Acta 1776:32–57

    PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Nilubol N, Zhang L, Shen M, Zhang Y, He M, Austin CP, Kebebew E (2012) Four clinically utilized drugs were identified and validated for treatment of adenocortical cancer using quantitative high-throughput screening. J Transl Med 10:1–15

    Article  CAS  Google Scholar 

  • Olej B, dos Santos NF, Leal L, Rumjanek VM (1998) Ouabain induces apoptosis on PHA-activated lymphocytes. Biosci Rep 18:1–7

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Prassas I, Karagiannis GS, Batruch I (2011) Digitoxin-induced cytotoxicity in cancer cells is mediated through distinct kinase and interferon signaling networks. Mol Cancer Ther 10:2083–2093

    Article  CAS  PubMed  Google Scholar 

  • Raghavendra PB, Sreenivasan Y, Ramesh GT, Manna SK (2007) Cardiac glycosides induced cell death via FasL by activating calcineurin and NF-AT, but apoptosis initially proceeds through activation of caspases. Apoptosis 12:307–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Siti Syarifah MM, Nurhanan MY, Abdul-Rahman PSA, Muhd Haffiz J, Asiah O, Mohd Ilham A (2014) Mechanisms of action of 17βH-neriifolin on its anticancer effects in SKOV-3 ovarian cancer cell line Anticancer Res 34: 4141–4152

    Google Scholar 

  • Steyn PS, Heerden FRV (1998) Bufadienolides of plant and animal origin. Nat Prod Rep 15:397–413

    Article  CAS  PubMed  Google Scholar 

  • Therien AG, Blostein R (2000) Mechanisms of sodium pump regulation. Am J Phys 279:541–567

    Article  Google Scholar 

  • Verheye-Dua F, Böhm L (1998) Na+,K+-ATPase inhibitor, ouabain accentuates irradiation damage in human tumour cell lines. Radiation Oncol Intervent 6:109–119

    Article  CAS  Google Scholar 

  • Xiao AY, Wei L, Xia S, Rothman S, SP Y (2002) Ionic mechanism of ouabain-induced concurrent apoptosis and necrosis in individual cultured cortical neurons. J Neurosci 22:1350–1362

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Yeh JY, Hunag WJ, Kan SF, Wang PS (2001) Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells. J Urol 166:1937–1942

    Article  CAS  PubMed  Google Scholar 

  • Zavareh RB, Lau KS, Hurren R, Datti A, Ashline DJ, Gronda M, Cheung P, Simpson CD, Liu W, Wasylishen AR, Boutros PC, Shi H, Vengopal A, Jurisica I, Penn LZ, Reinhold VN, Ezzat S, Wrana J, Rose DR, Schachter H, Dennis JW, Schimmer AD (2008) Inhibition of the sodium/potassium ATPase impairs N-glycan expression and function. Cancer Res 68:6688–6697

    Article  CAS  Google Scholar 

  • Zhang L, Nakaya K, Yoshida T, Kuroiwa Y (1992) Induction by bufalin of differentiation of human leukemia cells HL60, U937, and ML1 toward macrophage/monocyte-like cells and its potent synergistic effect on the differentiation of human leukemia cells in combination with other inducers. Cancer Res 52:4634–4641

    PubMed  CAS  Google Scholar 

  • Zhang H, Qian DZ, Tan YS, Lee KA, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu JO, Semenza GL (2008) Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proc Nat Acad Sci 105:19579–19586

    Article  PubMed  Google Scholar 

  • Zhao M, Bai L, Wang L, Toki A, Hasegawa T, Kikuchi M, Abe M, Jun-ichi S, Hasegawa R, Bai Y, Mitsui T, Ogura H, Kataoka T, Oka S, Tsushima H, Kiuchi M, Hirose K, Tomida A, Tsuruo T, Ando M (2007) Bioactive cardenolides from the stems and twigs of Nerium oleander. J Nat Prod 70:1098–1103

    Article  CAS  PubMed  Google Scholar 

Download references

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Authors and Affiliations

  1. Natural Products Division, Forest Research Institute Malaysia (FRIM), Kepong, 42109, Selangor, Malaysia

    Mohd Mutalip Siti-Syarifah & Yunos Nurhanan-Murni

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  1. Mohd Mutalip Siti-Syarifah
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  2. Yunos Nurhanan-Murni
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Correspondence to Mohd Mutalip Siti-Syarifah .

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Editors and Affiliations

  1. Department of Botany, Gandhi Faiz-e-Aam College, Shahjahanpur, Uttar Pradesh, India

    Mohd Sayeed Akhtar

  2. Department of Crop Science, Faculty of Agriculture, Universiti Putra Malaysia, Serdang, Selangor, Malaysia

    Mallappa Kumara Swamy

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Siti-Syarifah, M.M., Nurhanan-Murni, Y. (2018). Therapeutic Potential of Cardiac Glycosides Against Cancer. In: Akhtar, M., Swamy, M. (eds) Anticancer Plants: Natural Products and Biotechnological Implements. Springer, Singapore. https://doi.org/10.1007/978-981-10-8064-7_4

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