Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Experimental Hematology & Oncology
Published in: Experimental Hematology & Oncology 1/2012

Open Access 01-12-2012 | Review

Digitoxin and its analogs as novel cancer therapeutics

Authors: Hosam A Elbaz, Todd A Stueckle, William Tse, Yon Rojanasakul, Cerasela Zoica Dinu

Published in: Experimental Hematology & Oncology | Issue 1/2012

Login to get access

Abstract

A growing body of evidence indicates that digitoxin cardiac glycoside is a promising anticancer agent when used at therapeutic concentrations. Digitoxin has a prolonged half-life and a well-established clinical profile. New scientific avenues have shown that manipulating the chemical structure of the saccharide moiety of digitoxin leads to synthetic analogs with increased cytotoxic activity. However, the anticancer mechanism of digitoxin or synthetic analogs is still subject to study while concerns about digitoxin's cardiotoxicity preclude its clinical application in cancer therapeutics. This review focuses on digitoxin and its analogs, and their cytotoxicity against cancer cells. Moreover, a new perspective on the pharmacological aspects of digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.
Appendix
Available only for authorised users
Literature
1.
Prassas I, Diamandis EP: Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 2008,7(11):926–935. 10.1038/nrd2682PubMedCrossRef
2.
Newman RA, Yang P, Pawlus AD, Block KI: Cardiac Glycosides as Novel Cancer Therapeutic Agents. Mol Interv 2008,8(1):36–49. 10.1124/mi.8.1.8PubMedCrossRef
3.
Huxtable RJ: The Erroneous Pharmacology of a Cat. Mol Interv 2001,1(2):75–77.PubMed
4.
Gheorghiade M, van Veldhuisen DJ, Colucci WS: Contemporary Use of Digoxin in the Management of Cardiovascular Disorders. Circulation 2006,113(21):2556–2564. 10.1161/CIRCULATIONAHA.105.560110PubMedCrossRef
5.
Rahimtoola SH, Tak T: The use of digitalis in heart failure. Curr Probl Cardiol 1996,21(12):781–853. 10.1016/S0146-2806(96)80001-6PubMedCrossRef
6.
Schonfeld W: The lead structure in cardiac glycosides is 5[beta],14[beta]-androstane-3[beta]14-diol. Naunyn Schmiedebergs Arch Pharmacol 1985, 329: 414–426. 10.1007/BF00496377PubMedCrossRef
7.
Melero CP, Medardea M, Feliciano AS: A short review on cardiotonic steroids and their aminoguanidine analogues. Molecules 2000, 5: 51–81. 10.3390/50100051CrossRef
8.
Langenhan JM, Peters NR, Guzei IA, Hoffmann M, Thorson JS: Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization. Proc Natl Acad Sci USA 2005,102(35):12305–12310. 10.1073/pnas.0503270102PubMedCentralPubMedCrossRef
9.
Iyer AKV, Zhou M, Azad N, Elbaz H, Wang L, Rogalsky DK, Rojanasakul Y, O'Doherty GA, Langenhan JM: A Direct Comparison of the Anticancer Activities of Digitoxin MeON-Neoglycosides and O-Glycosides: Oligosaccharide Chain Length-Dependent Induction of Caspase-9-Mediated Apoptosis. ACS Med Chem Lett 2010,1(7):326–330. 10.1021/ml1000933PubMedCentralPubMedCrossRef
10.
Barry W, Hasin Y, Smith T: Sodium pump inhibition, enhanced calcium influx via sodium-calcium exchange, and positive inotropic response in cultured heart cells. Circ Res 1985,56(2):231–241.PubMedCrossRef
11.
Kaplan JH: Biochemistry of Na, K-ATPase. Annu Rev Biochem 2002, 71: 511–535. 10.1146/annurev.biochem.71.102201.141218PubMedCrossRef
12.
Kaplan JG: Membrane cation transport and the control of proliferation of mammalian cells. Annu Rev Physiol 1978, 40: 19–41. 10.1146/annurev.ph.40.030178.000315PubMedCrossRef
13.
Brewer H: Historical perspectives on health. J R Soc Promot Health 2004,124(4):184–187. 10.1177/146642400412400412PubMedCrossRef
14.
Watabe M, Masuda Y, Nakajo S, Yoshida T, Kuroiwa Y, Nakaya K: The Cooperative Interaction of Two Different Signaling Pathways in Response to Bufalin Induces Apoptosis in Human Leukemia U937 Cells. J Biol Chem 1996,271(24):14067–14073. 10.1074/jbc.271.24.14067PubMedCrossRef
15.
Yeh JY, Huang WJ, Kan SF, Wang PS: Effects of bufalin and cinobufagin on the proliferation of androgen dependent and independent prostate cancer cells. Prostate 2003,54(2):112–124. 10.1002/pros.10172PubMedCrossRef
16.
Han KQ: Anti-tumor activities and apoptosis-regulated mechanisms of bufalin on the orthotopic transplantation tumor model of human hepatocellular carcinoma in nude mice. World J Gastroenterol 2007, 13: 3374–3379.PubMedCentralPubMedCrossRef
17.
Shiratori O: Growth inhibitory effect of cardiac glycosides and aglycones on neoplastic cells: in vitro and in vivo studies. Gann 1967,58(6):521–528.PubMed
18.
López-Lázaro M: Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved. Expert Opin Ther Targets 2007,11(8):1043–1053. 10.1517/14728222.11.8.1043PubMedCrossRef
19.
20.
Stenkvist B: Evidence of a modifying influence of heart glucosides on the development of breast cancer. Anal Quant Cytol 1980, 2: 49–54.PubMed
21.
Stenkvist B: Cardiac glycosides and breast cancer, revisited. N Engl J Med 1982, 306: 484.PubMed
22.
Stenkvist B: Is digitalis a therapy for breast carcinoma? Oncol Rep 1999, 6: 493–496.PubMed
23.
24.
Hashimoto S, Jing Y, Kawazoe N, Masuda Y, Nakajo S, Yoshida T, Kuroiwa Y, Nakaya K: Bufalin reduces the level of topoisomerase II in human leukemia cells and affects the cytotoxicity of anticancer drugs. Leuk Res 1997,21(9):875–883. 10.1016/S0145-2126(97)00061-1PubMedCrossRef
25.
Jing Y: Selective inhibitory effect of bufalin on growth of human tumor cells in vitro: association with the induction of apoptosis in leukemia HL-60 cells. Jpn J Cancer Res 1994, 85: 645–651. 10.1111/j.1349-7006.1994.tb02408.xPubMedCrossRef
26.
Kamano Y, Kotake A, Hashima H, Inoue M, Morita H, Takeya K, Itokawa H, Nandachi N, Segawa T, Yukita A, et al.: Structure-cytotoxic activity relationship for the toad poison bufadienolides. Bioorg Med Chem 1998,6(7):1103–1115. 10.1016/S0968-0896(98)00067-4PubMedCrossRef
27.
Kawazoe N, Watabe M, Masuda Y, Nakajo S, Nakaya K: Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells. Oncogene 1999, 18: 2413–2421. 10.1038/sj.onc.1202555PubMedCrossRef
28.
Masuda Y: Bufalin induces apoptosis and influences the expression of apoptosis-related genes in human leukemia cells. Leuk Res 1995, 19: 549–556. 10.1016/0145-2126(95)00031-IPubMedCrossRef
29.
Bielawski K, Winnicka K, Bielawska A: 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 2006,29(7):1493–1497. 10.1248/bpb.29.1493PubMedCrossRef
30.
Johansson S, Lindholm P, Gullbo J, Larsson P, Bohlin L, Claeson P: Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anti-Cancer Drugs 2001,12(5):475–483. 10.1097/00001813-200106000-00009PubMedCrossRef
31.
Lopez-Lazaro M, Pastor N, Azrak SS, Ayuso MJ, Austin CA, Cortes F: Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients. J Nat Prod 2005,68(11):1642–1645. 10.1021/np050226lPubMedCrossRef
32.
Winnicka K, Bielawski K, Bielawska A, Miltyk W: Apoptosis-mediated cytotoxicity of ouabain, digoxin and proscillaridin A in the estrogen independent MDA-MB-231 breast cancer cells. Arch Pharm Res 2007, 30: 1216–1224. 10.1007/BF02980262PubMedCrossRef
33.
Winnicka K, Bielawski K, Bielawska A, Miltyk W: Dual effects of ouabain, digoxin and proscillaridin A on the regulation of apoptosis in human fibroblasts. Nat Prod Res 2010,24(3):274–285. 10.1080/14786410902991878PubMedCrossRef
34.
Yeh JY, Huang WJ, Kan SF, Wang PS: Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells. J Urol 2001,166(5):1937–1942. 10.1016/S0022-5347(05)65724-2PubMedCrossRef
35.
Zhang HF, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammer H, Chang D, Pili R, et al.: Digoxin and other cardiac glycosides inhibit HIF-1 alpha synthesis and block tumor growth. Proc Natl Acad Sci USA 2008,105(50):19579–19586. 10.1073/pnas.0809763105PubMedCentralPubMedCrossRef
36.
Elbaz HA, Stueckle TA, Wang H-YL, O'Doherty G, Lowry DT, Sargent LM, Wang L, Dinu CZ, Rojanasakul Y: Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells. Toxicology and Applied Pharmacology 2012,258(1):51–60. 10.1016/j.taap.2011.10.007PubMedCentralPubMedCrossRef
37.
Wang H-YL, Rojanasakul Y, O‚ÄôDoherty GA: Synthesis and Evaluation of the α-d-/α-l-Rhamnosyl and Amicetosyl Digitoxigenin Oligomers as Antitumor Agents. ACS Med Chem Lett 2011,2(4):264–269. 10.1021/ml100290dPubMedCentralPubMedCrossRef
38.
Wang H-YL, Wu B, Zhang Q, Kang S-W, Rojanasakul Y, O‚ÄôDoherty GA: C5'-Alkyl Substitution Effects on Digitoxigenin α-l-Glycoside Cancer Cytotoxicity. ACS Med Chem Lett 2011,2(4):259–263. 10.1021/ml100291nPubMedCentralPubMedCrossRef
39.
Wang H-YL, Xin W, Zhou M, Stueckle TA, Rojanasakul Y, O'Doherty GA: Stereochemical Survey of Digitoxin Monosaccharides. ACS Med Chem Lett 2010,2(1):73–78.PubMedCentralCrossRef
40.
Wang Z, Zheng M, Li Z, Li R, Jia L, Xiong X, Southall N, Wang S, Xia M, Austin CP, et al.: Cardiac Glycosides Inhibit p53 Synthesis by a Mechanism Relieved by Src or MAPK Inhibition. Cancer Res 2009,69(16):6556–6564. 10.1158/0008-5472.CAN-09-0891PubMedCentralPubMedCrossRef
41.
Winnicka K, Bielawski K, Bielawska A, Miltyk W: Dual effects of ouabain, digoxin and proscillaridin A on the regulation of apoptosis in human fibroblasts. Nat Prod Res 2010,24(3):274–285. 10.1080/14786410902991878PubMedCrossRef
42.
Afaq F, Saleem M, Aziz MH, Mukhtar H: Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin. Toxicol Appl Pharmacol 2004,195(3):361–369. 10.1016/j.taap.2003.09.027PubMedCrossRef
43.
Felth J, Rickardson L, Rosen J, Wickstrom M, Fryknas M, Lindskog M, Bohlin L, Gullbo J: Cytotoxic Effects of Cardiac Glycosides in Colon Cancer Cells, Alone and in Combination with Standard Chemotherapeutic Drugs. J Nat Prod 2009,72(11):1969–1974. 10.1021/np900210mPubMedCrossRef
44.
Gupta RS, Chopra A, Stetsko DK: Cellular basis for the species differences in sensitivity to cardiac glycosides (digitalis). J Cell Physiol 1986,127(2):197–206. 10.1002/jcp.1041270202PubMedCrossRef
45.
Manna SK, Sah NK, Newman RA, Cisneros A, Aggarwal BB: Oleandrin suppresses activation of nuclear transcription factor-kappa B, activator protein-1, and c-Jun NH2-terminal kinase. Cancer Res 2000,60(14):3838–3847.PubMed
46.
McConkey DJ, Lin Y, Nutt LK, Ozel HZ, Newman RA: Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res 2000,60(14):3807–3812.PubMed
47.
Nasu S, Milas L, Kawabe S, Raju U, Newman RA: Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process. Cancer Lett 2002,185(2):145–151. 10.1016/S0304-3835(02)00263-XPubMedCrossRef
48.
Newman RA: Oleandrin-mediated oxidative stress in human melanoma cells. J Exp Ther Oncol 2006, 5: 167–181.PubMed
49.
Newman RA, Kondo Y, Yokoyama T, Dixon S, Cartwright C, Chan D, Johansen M, Yang P: Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integr Cancer Ther 2007, 6: 354–364. 10.1177/1534735407309623PubMedCrossRef
50.
Pathak S, Multani AS, Narayan S, Kumar V, Newman RA: AnvirzelTM, an extract of Nerium oleander, induces cell death in human but not murine cancer cells. Anti-Cancer Drugs 2000,11(6):455–463. 10.1097/00001813-200007000-00006PubMedCrossRef
51.
Raghavendra PB, Sreenivasan Y, Manna SK: Oleandrin induces apoptosis in human, but not in murine cells: Dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity. Mol Immunol 2007,44(9):2292–2302. 10.1016/j.molimm.2006.11.009PubMedCrossRef
52.
Schoner W, Scheiner-Bobis G: Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth. Am J Physiol Cell Physiol 2007,293(2):C509-C536. 10.1152/ajpcell.00098.2007PubMedCrossRef
53.
Smith JA, Madden T, Vijjeswarapu M, Newman RA: Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin. Biochem Pharmacol 2001,62(4):469–472. 10.1016/S0006-2952(01)00690-6PubMedCrossRef
54.
Sreenivasan Y, Raghavendra PB, Manna SK: Oleandrin-mediated expression of fas potentiates apoptosis in tumor cells. J Clin Immunol 2006,26(4):308–322. 10.1007/s10875-006-9028-0PubMedCrossRef
55.
Sreenivasan Y, Sarkar A, Manna SK: Oleandrin suppresses activation of nuclear transcription factor-kappa B and activator protein-1 and potentiates apoptosis induced by ceramide. Biochem Pharmacol 2003,66(11):2223–2239. 10.1016/j.bcp.2003.07.010PubMedCrossRef
56.
Wang XM, Plomley JB, Newman RA, Cisneros A: LC/MS/MS analyses of an oleander extract for cancer treatment. Anal Chem 2000,72(15):3547–3552. 10.1021/ac991425aPubMedCrossRef
57.
Yang PY, Menter DG, Cartwright C, Chan D, Dixon S, Suraokar M, Mendoza G, Llansa N, Newman RA: Oleandrin-mediated inhibition of human tumor cell proliferation: importance of Na, K-ATPase alpha subunits as drug targets. Mol Cancer Ther 2009,8(8):2319–2328. 10.1158/1535-7163.MCT-08-1085PubMedCrossRef
58.
Kometiani P, Liu L, Askari A: Digitalis-Induced Signaling by Na+/K + -ATPase in Human Breast Cancer Cells. Mol Pharmacol 2005,67(3):929–936.PubMedCrossRef
59.
Lawrence TS: Ouabain sensitizes tumor cells but not normal cells to radiation. Int J Radiat Oncol Biol Phys 1988,15(4):953–958. 10.1016/0360-3016(88)90132-0PubMedCrossRef
60.
Winnicka K, Bielawski K, Bielawska A, Surazy ≈ Ñski A: Antiproliferative activity of derivatives of ouabain, digoxin and proscillaridin A in human MCF-7 and MDA-MB-231 breast cancer cells. Biol Pharm Bull 2008,31(6):1131–1140. 10.1248/bpb.31.1131PubMedCrossRef
61.
Xie Z, Kometiani P, Liu J, Li J, Shapiro JI, Askari A: Intracellular reactive oxygen species mediate the linkage of Na+/K + -ATPase to hypertrophy and its marker genes in cardiac myocytes. J Biol Chem 1999,274(27):19323–19328. 10.1074/jbc.274.27.19323PubMedCrossRef
62.
Xu J-W, Jin R-M, Wang Y-R, Lin W, Meng B: Effects of ouabain at different concentrations on growth of leukemia cells. Zhongguo Dang Dai Er Ke Za Zhi 2009,11(4):259–262.PubMed
63.
Contreras RG, Flores-Maldonado C, Lázaro A, Shoshani L, Flores-Benitez D, Larré I, Cereijido M: Ouabain Binding to Na+/K + -ATPase Relaxes Cell Attachment and Sends a SpecificSignal (NACos) to the Nucleus. J Membr Biol 2004,198(3):147–158. 10.1007/s00232-004-0670-2PubMedCrossRef
64.
Johansson S, Lindholm P, Gullbo J, Larsson R, Bohlin L, Claeson P: Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anti-Cancer Drugs 2001,12(5):475–483. 10.1097/00001813-200106000-00009PubMedCrossRef
65.
Schneider R: Proscillaridin A immunoreactivity: its purification, transport in blood by a specific binding protein and its correlation with blood pressure. Clin Exp Hypertens 1998, 20: 593–599. 10.3109/10641969809053237PubMedCrossRef
66.
Winnicka K, Bielawski K, Bielawska A, Surazynski A: Antiproliferative activity of derivatives of ouabain, digoxin and proscillaridin a in human MCF-7 and MDA-MB-231 breast cancer cells. Biol Pharm Bull 2008,31(6):1131–1140. 10.1248/bpb.31.1131PubMedCrossRef
67.
Belz GG: Breithaupt-Gr√∂gler K, Osowski U: Treatment of congestive heart failure-current status of use of digitoxin. Eur J Clin Invest 2001,31(Suppl 2):10–17.PubMedCrossRef
68.
Castle MC: Pharmacokinetics of digoxin and digitoxin in humans. Eastern virginia med sch/med col hamp rd 1977.
69.
BøHMER T, RøSETH A: Prolonged digitoxin half-life in very elderly patients. Age Ageing 1998,27(2):222–224. 10.1093/ageing/27.2.222PubMedCrossRef
70.
Smith TW: Digitalis toxicity: epidemiology and clinical use of serum concentration measurements. Am J Med 1975,58(4):470–476. 10.1016/0002-9343(75)90118-7PubMedCrossRef
71.
Williams JF Jr, Potter RD, Mathew B: Effects of arrhythmia-producing concentrations of digitoxin on mechanical performance of cat myocardium. Am Heart J 1983,105(1):21–25. 10.1016/0002-8703(83)90273-9PubMedCrossRef
72.
Haux J: Digitoxin is a potential anticancer agent for several types of cancer. Med Hypotheses 1999,53(6):543–548. 10.1054/mehy.1999.0985PubMedCrossRef
73.
Schatzmann HJ, Rass B: Inhibition of the active Na-K-transport and Na-K-activated membrane ATP-ase of erythrocyte stroma by ouabain. Helv Physiol Pharmacol Acta 1965, 65: C47-C49.PubMed
74.
Chang HT, Huang JK, Wang JL, Cheng JS, Lee KC, Lo YK, Liu CP, Chou KJ, Chen WC, Su W, et al.: Tamoxifen-induced increases in cytoplasmic free Ca-2+ levels in human breast cancer cells. Breast Cancer Res Treat 2002,71(2):125–131. 10.1023/A:1013807731642PubMedCrossRef
75.
Koumura T, Nakamura C, Nakagawa Y: Role of calcium-induced mitochondrial hydroperoxide in induction of apoptosis of RBL2H3 cells with eicosapentaenoic acid treatment. Free Radic Res 2005,39(10):1083–1089. 10.1080/10715760500264654PubMedCrossRef
76.
Pigozzi D, Tombal B, Ducret T, Vacher P, Gailly P: Role of store-dependent influx of Ca2+ and efflux of K + in apoptosis of CHO cells. Cell Calcium 2004,36(5):421–430. 10.1016/j.ceca.2004.04.002PubMedCrossRef
77.
Xie Z, Cai T: Na+/K + ATPase-Mediated Signal Transduction: From Protein Interaction to Cellular Function. Mol Interv 2003,3(3):157–168. 10.1124/mi.3.3.157PubMedCrossRef
78.
Wang XQ: Apoptotic insults impair Na+, K + -ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress. J Cell Sci 2003, 116: 2099–2110. 10.1242/jcs.00420PubMedCrossRef
79.
Liu L, Abramowitz J, Askari A, Allen JC: Role of caveolae in ouabain-induced proliferation of cultured vascular smooth muscle cells of the synthetic phenotype. Am J Physiol Heart Circ Physiol 2004, 287: H2173-H2182. 10.1152/ajpheart.00352.2004PubMedCrossRef
80.
Barwe SP: Novel role for Na, K-ATPase in phosphatidylinositol 3-kinase signaling and suppression of cell motility. Mol Biol Cell 2005, 16: 1082–1094. 10.1091/mbc.E04-05-0427PubMedCentralPubMedCrossRef
81.
Larre I, Lazaro A, Contreras RG, Balda MS, Matter K, Flores-Maldonado C, Ponce A, Flores-Benitez D, Rincon-Heredia R, Padilla-Benavides T, et al.: Ouabain modulates epithelial cell tight junction. Proc Natl Acad Sci 2010,107(25):11387–11392. 10.1073/pnas.1000500107PubMedCentralPubMedCrossRef
82.
Bulavin DV, Fornace AJ Jr: p38 MAP kinase's emerging role as a tumor suppressor. Adv Cancer Res 2004, 92: 95–118.PubMedCrossRef
83.
Cagnol S, Chambard J-C: ERK and cell death: mechanisms of ERK-induced cell death-apoptosis, autophagy and senescence. FEBS J 2009,277(1):2–21.PubMedCrossRef
84.
de Paula RM, Lamb TM, Bennett L, Bell-Pedersen D: A connection between MAPK pathways and circadian clocks. Cell Cycle 2008,7(17):2630–2634. 10.4161/cc.7.17.6516PubMedCentralPubMedCrossRef
85.
Gotoh I, Nishida E: Signal transductions by the MAP kinase cascades. Nippon Rinsho 1998,56(7):1779–1783.PubMed
86.
Han J, Sun P: The pathways to tumor suppression via route p38. Trends Biochem Sci 2007,32(8):364–371. 10.1016/j.tibs.2007.06.007PubMedCrossRef
87.
Keyse SM: Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev 2008,27(2):253–261. 10.1007/s10555-008-9123-1PubMedCrossRef
88.
Khavari TA, Rinn J: Ras/Erk MAPK signaling in epidermal homeostasis and neoplasia. Cell Cycle 2007,6(23):2928–2931. 10.4161/cc.6.23.4998PubMedCrossRef
89.
Bolós V, Gasent JM, López-Tarruella S, Grande E: The dual kinase complex FAK-Src as a promising therapeutic target in cancer. Onco Targets Ther 2010, 3: 83–97.PubMedCentralPubMedCrossRef
90.
Burnham MR, Bruce-Staskal PJ, Harte MT, Weidow CL, Ma A, Weed SA, Bouton AH: Regulation of c-SRC activity and function by the adapter protein CAS. Mol Cell Biol 2000,20(16):5865–5878. 10.1128/MCB.20.16.5865-5878.2000PubMedCentralPubMedCrossRef
91.
Chen C-Y, Chang C-Y, Liu H-J, Liao M-H, Chang C-I, Hsu J-L, Shih W-L: Apoptosis induction in BEFV-infected Vero and MDBK cells through Src-dependent JNK activation regulates caspase-3 and mitochondria pathways. Vet Res 2010.,41(2):
92.
Di Florio A, Capurso G, Milione M, Panzuto F, Geremia R: Delle Fave G, Sette C: Src family kinase activity regulates adhesion, spreading and migration of pancreatic endocrine tumour cells. Endocr Relat Cancer 2007,14(1):111–124. 10.1677/erc.1.01318PubMedCrossRef
93.
Götz R: Inter-cellular adhesion disruption and the RAS/RAF and beta-catenin signalling in lung cancer progression. Cancer Cell Int 2008,8(1):7. 10.1186/1475-2867-8-7PubMedCentralPubMedCrossRef
94.
Liu Y, Gao L, Gelman IH: SSeCKS/Gravin/AKAP12 attenuates expression of proliferative and angiogenic genes during suppression of v-Src-induced oncogenesis. BMC Cancer 2006,6(1):105. 10.1186/1471-2407-6-105PubMedCentralPubMedCrossRef
95.
Owen KA, Abshire MY, Tilghman RW, Casanova JE, Bouton AH: FAK Regulates Intestinal Epithelial Cell Survival and Proliferation during Mucosal Wound Healing. PLoS One 2011.,6(8):
96.
97.
Williams SP, Karnezis T, Achen MG, Stacker SA: Targeting lymphatic vessel functions through tyrosine kinases. J Angiogenes Res 2010, 2: 13–13. 10.1186/2040-2384-2-13PubMedCentralPubMedCrossRef
98.
Liang M, Cai T, Tian J, Qu W, Xie ZJ: Functional characterization of Src-interacting Na/K-ATPase using RNA interference assay. J Biol Chem 2006, 281: 19709–19719. 10.1074/jbc.M512240200PubMedCrossRef
99.
Langenhan JM, Engle JM, Slevin LK, Fay LR, Lucker RW, Smith KR, Endo MM: Modifying the glycosidic linkage in digitoxin analogs provides selective cytotoxins. Bioorg Med Chem Lett 2008,18(2):670–673. 10.1016/j.bmcl.2007.11.058PubMedCrossRef
100.
Zhou M, O'Doherty G: The De novo Synthesis of Oligosaccharides - Application to the Medicinal Chemistry SAR Study of Digitoxin. ChemInform Abstract 2008.,39(27):
101.
Zhou M, O'Doherty G: The De Novo Synthesis of Oligosaccharides: Application to the Medicinal Chemistry SAR-Study of Digitoxin. Curr Top Med Chem 2008, 8: 114–125. 10.2174/156802608783378828PubMedCrossRef
102.
Mohammadi K, Kometiani P, Xie Z, Askari A: Role of protein kinase C in the signal pathways that link Na+/K + -ATPase to ERK1/2. J Biol Chem 2001, 276: 42050–42056. 10.1074/jbc.M107892200PubMedCrossRef
103.
Yuan Z: Na/K-ATPase tethers phospholipase C and IP3 receptor into a calcium-regulatory complex. Mol Biol Cell 2005, 16: 4034–4045. 10.1091/mbc.E05-04-0295PubMedCentralPubMedCrossRef
104.
Liu L, Askari A: On the importance and mechanism of amplification of digitalis signal through Na+/K+-ATPase. Cell Mol Biol (Noisy-le-Grand) 2006,52(8):28–30.
105.
Kometiani P, Li J, Gnudi L, Kahn BB, Askari A, Xie Z: Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases. J Biol Chem 1998,273(24):15249–15256. 10.1074/jbc.273.24.15249PubMedCrossRef
106.
Peng M, Huang L, Xie Z, Huang WH, Askari A: Partial inhibition of Na+/K + -ATPase by ouabain induces the Ca2 + -dependent expressions of early-response genes in cardiac myocytes. J Biol Chem 1996,271(17):10372–10378. 10.1074/jbc.271.17.10372PubMedCrossRef
107.
Schoner W, Scheiner-Bobis G: Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth. Am J Physiol Cell Physiol 2007,293(2):C509-C536. 10.1152/ajpcell.00098.2007PubMedCrossRef
108.
Dueñas-González A, García-López P, Herrera LA, Medina-Franco JL, González-Fierro A, Myrna C: The prince and the pauper. A tale of anticancer targeted agents. Mol Cancer 2008,7(1):82. 10.1186/1476-4598-7-82PubMedCentralPubMedCrossRef
109.
Shull MM, Pugh DG, Lingrel JB: Characterization of the human Na, K-ATPase alpha 2 gene and identification of intragenic restriction fragment length polymorphisms. J Biol Chem 1989,264(29):17532–17543.PubMed
110.
Jagielska J, Salguero G, Schieffer B, Bavendiek U: Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis? Atherosclerosis 2009,206(2):390–396. 10.1016/j.atherosclerosis.2009.03.019PubMedCrossRef
111.
Srivastava M, Eidelman O, Zhang J, Paweletz C, Caohuy H, Yang Q, Jacobson KA, Heldman E, Huang W, Jozwik C, et al.: Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. Proc Natl Acad Sci USA 2004,101(20):7693–7698. 10.1073/pnas.0402030101PubMedCentralPubMedCrossRef
112.
Yang Q, Huang W, Jozwik C, Lin Y, Glasman M, Caohuy H, Srivastava M, Esposito D, Gillette W, Hartley J, et al.: 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 USA 2005,102(27):9631–9636. 10.1073/pnas.0504097102PubMedCentralPubMedCrossRef
113.
Bamberger AM, Milde-Langosch K, R√∂ssing E, Goemann C, L√∂ning T: Expression pattern of the AP-1 family in endometrial cancer: correlations with cell cycle regulators. J Cancer Res Clin Oncol 2001,127(9):545–550. 10.1007/s004320100255PubMedCrossRef
114.
Dumesic PA, Scholl FA, Barragan DI, Khavari PA: Erk1/2 MAP kinases are required for epidermal G2/M progression. J Cell Biol 2009,185(3):409–422. 10.1083/jcb.200804038PubMedCentralPubMedCrossRef
115.
Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG: The Activator Protein-1 Transcription Factor in Respiratory Epithelium Carcinogenesis. Mol Cancer Res 2007,5(2):109–120. 10.1158/1541-7786.MCR-06-0311PubMedCrossRef
116.
Crombez L, Morris MC, Dufort S, Aldrian-Herrada G, Nguyen Q, Mc Master G, Coll J-L, Heitz F, Divita G: Targeting cyclin B1 through peptide-based delivery of siRNA prevents tumour growth. Nucleic Acids Res 2009,37(14):4559–4569. 10.1093/nar/gkp451PubMedCentralPubMedCrossRef
117.
Yuan J, Yan R, Kramer A, Eckerdt F, Roller M, Kaufmann M, Strebhardt K: Cyclin B1 depletion inhibits proliferation and induces apoptosis in human tumor cells. Oncogene 2004,23(34):5843–5852. 10.1038/sj.onc.1207757PubMedCrossRef
118.
Chae SW, Sohn JH, Kim D-H, Choi YJ, Park YL, Kim K, Cho YH, Pyo J-S, Kim JH: Overexpressions of Cyclin B1, cdc2, p16 and p53 in Human Breast Cancer: The Clinicopathologic Correlations and Prognostic Implications. Yonsei Med J 2011,52(3):445–453. 10.3349/ymj.2011.52.3.445PubMedCentralPubMedCrossRef
119.
Cooper WA, Kohonen-Corish MRJ, McCaughan B, Kennedy C, Sutherland RL, Lee CS: Expression and prognostic significance of cyclin B1 and cyclin A in non-small cell lung cancer. Histopathology 2009,55(1):28–36. 10.1111/j.1365-2559.2009.03331.xPubMedCrossRef
120.
Egloff AM, Weissfeld J, Land SR, Finn OJ: Evaluation of anticyclin B1 serum antibody as a diagnostic and prognostic biomarker for lung cancer. Ann N Y Acad Sci 2005, 1062: 29–40. 10.1196/annals.1358.005PubMedCrossRef
121.
Kim D-H: Prognostic implications of cyclin B1, p34cdc2, p27(Kip1) and p53 expression in gastric cancer. Yonsei Med J 2007,48(4):694–700. 10.3349/ymj.2007.48.4.694PubMedCentralPubMedCrossRef
122.
Wong Y-F, Cheung T-H, Tsao GSW, Lo KWK, Yim S-F, Wang VW, Heung MMS, Chan SCS, Chan LKY, Ho TWF, et al.: Genome-wide gene expression profiling of cervical cancer in Hong Kong women by oligonucleotide microarray. Int J Cancer 2006,118(10):2461–2469. 10.1002/ijc.21660PubMedCrossRef
123.
Yoshida T, Tanaka S, Mogi A, Shitara Y, Kuwano H: The clinical significance of Cyclin B1 and Wee1 expression in non-small-cell lung cancer. Ann Oncol 2004,15(2):252–256. 10.1093/annonc/mdh073PubMedCrossRef
124.
De Souza CP, Ellem KA, Gabrielli BG: Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events. Exp Cell Res 2000,257(1):11–21. 10.1006/excr.2000.4872PubMedCrossRef
125.
Stark G, Taylor W: Control of the G2/M transition. Mol Biotechnol 2006,32(3):227–248. 10.1385/MB:32:3:227PubMedCrossRef
126.
Dabrowski A, Filip A, Zgodzi ≈ Ñski W, Dabrowska M, Pola ≈ Ñska D, W√ ≥ jcik M, Zinkiewicz K, Wallner G: Assessment of prognostic significance of cytoplasmic survivin expression in advanced oesophageal cancer. Folia Histochem Cytobiol 2004,42(3):169–172.PubMed
127.
Falleni M, Pellegrini C, Marchetti A, Oprandi B, Buttitta F, Barassi F, Santambrogio L, Coggi G, Bosari S: Survivin gene expression in early-stage non-small cell lung cancer. J Pathol 2003,200(5):620–626. 10.1002/path.1388PubMedCrossRef
128.
He L, Hou M, Zhang J, Xu N, Chen P: Subcellular localization of survivin in non-small cell lung cancer. Ai Zheng 2009,28(9):955–960.PubMed
129.
Y-j R, Q-y Z: Expression of survivin and its clinical significance in non-small cell lung cancer. Beijing Da Xue Xue Bao 2005,37(5):504–507.
130.
Yang H, Fu J-h, Hu Y, Huang W-z, Zheng B, Wang G: Relationship between survivin expression and chemosensitivity of human lung cancer cells. Zhonghua Yi Xue Za Zhi 2007,87(27):1934–1937.PubMed
131.
Zhou J-M, Zhou J-H, Deng Z-H, Zheng H, Jiang H-Y, Cao H-Q: Expression of survivin and proliferating cell nuclear antigen in human non-small cell lung cancer. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2005,30(5):544–548.PubMed
132.
Beardmore VA, Ahonen LJ, Gorbsky GJ, Kallio MJ: Survivin dynamics increases at centromeres during G2/M phase transition and is regulated by microtubule-attachment and Aurora B kinase activity. J Cell Sci 2004,117(Pt 18):4033–4042.PubMedCrossRef
133.
Beltrami E, Plescia J, Wilkinson JC, Duckett CS, Altieri DC: Acute Ablation of Survivin Uncovers p53-dependent Mitotic Checkpoint Functions and Control of Mitochondrial Apoptosis. J Biol Chem 2004,279(3):2077–2084. 10.1074/jbc.M309479200PubMedCrossRef
134.
Mita AC, Mita MM, Nawrocki ST, Giles FJ: Survivin: Key Regulator of Mitosis and Apoptosis and Novel Target for Cancer Therapeutics. Clin Cancer Res 2008,14(16):5000–5005. 10.1158/1078-0432.CCR-08-0746PubMedCrossRef
135.
Wolanin K, Piwocka K: Role of survivin in mitosis. Postepy Biochem 2007,53(1):10–18.PubMed
136.
Colnaghi R, Wheatley SP: Liaisons between survivin and Plk1 during cell division and cell death. J Biol Chem 2010,285(29):22592–22604. 10.1074/jbc.M109.065003PubMedCentralPubMedCrossRef
137.
Lens SMA, Wolthuis RMF, Klompmaker R, Kauw J, Agami R, Brummelkamp T, Kops G, Medema RH: Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO J 2003,22(12):2934–2947. 10.1093/emboj/cdg307PubMedCentralPubMedCrossRef
138.
Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S, Villa A, Marchisio PC, Altieri DC: Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nat Cell Biol 1999,1(8):461–466. 10.1038/70242PubMedCrossRef
139.
Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998,396(6711):580–584. 10.1038/25141PubMedCrossRef
140.
Castedo M, Perfettini J-L, Roumier T, Andreau K, Medema R, Kroemer G: Cell death by mitotic catastrophe: a molecular definition. Oncogene 2004,23(16):2825–2837. 10.1038/sj.onc.1207528PubMedCrossRef
141.
Okada H, Mak TW: Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 2004,4(8):592–603. 10.1038/nrc1412PubMedCrossRef
142.
Vakifahmetoglu H, Olsson M, Zhivotovsky B: Death through a tragedy: mitotic catastrophe. Cell Death Differ 2008,15(7):1153–1162. 10.1038/cdd.2008.47PubMedCrossRef
143.
Barre' B, Perkins ND: A cell cycle regulatory network controlling NF-kappaB subunit activity and function. EMBO J 2007,26(23):4841–4855. 10.1038/sj.emboj.7601899CrossRef
144.
Bartek J, Lukas J: Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 2003, 3: 421–429. 10.1016/S1535-6108(03)00110-7PubMedCrossRef
145.
Zhou B-BS, Bartek J: Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer 2004,4(3):216–225. 10.1038/nrc1296PubMedCrossRef
146.
Zhou B-BS, Sausville EA: Drug discovery targeting Chk1 and Chk2 kinases. Prog Cell Cycle Res 2003, 5: 413–421.PubMed
147.
Haas M, Wang H, Tian J, Xie Z: Src-mediated inter-receptor cross-talk between the Na+/K + -ATPase and the epidermal growth factor receptor relays the signal from ouabain to mitogen-activated protein kinases. J Biol Chem 2002, 277: 18694–18702. 10.1074/jbc.M111357200PubMedCrossRef
Metadata
Title
Digitoxin and its analogs as novel cancer therapeutics
Authors
Hosam A Elbaz
Todd A Stueckle
William Tse
Yon Rojanasakul
Cerasela Zoica Dinu
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Experimental Hematology & Oncology / Issue 1/2012
Electronic ISSN: 2162-3619
DOI
https://doi.org/10.1186/2162-3619-1-4

Other articles of this Issue 1/2012

Experimental Hematology & Oncology 1/2012 Go to the issue

Rapid communication

JAK2V617F and p53 mutations coexist in erythroleukemia and megakaryoblastic leukemic cell lines

Research

Ratio of involved/uninvolved immunoglobulin quantification by Hevylite™ assay: clinical and prognostic impact in multiple myeloma

Case report

Treatment of splenic marginal zone lymphoma of the CNS with high-dose therapy and allogeneic stem cell transplantation

Review

The role of BCL11B in hematological malignancy

Letter to the Editor

Immune modulation therapy in the management of bortezomib-induced peripheral neuropathy

Case report

Association of radiotherapy with preferential depletion of luminal epithelial cells in a BRCA1 mutation carrier
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits