Ex Vivo Activity of Cardiac Glycosides in Acute Leukaemia

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Jan 20

PMID 21246039

Citations 10

Authors

Helene Hallbook

Jenny Felth

Anna Eriksson

Marten Fryknas

Lars Bohlin

Rolf Larsson

Joachim Gullbo

Affiliations

Soon will be listed here.

Abstract

Background: Despite years of interest in the anti-cancerous effects of cardiac glycosides (CGs), and numerous studies in vitro and in animals, it has not yet been possible to utilize this potential clinically. Reports have demonstrated promising in vitro effects on different targets as well as a possible therapeutic index/selectivity in vitro and in experimental animals. Recently, however, general inhibition of protein synthesis was suggested as the main mechanism of the anti-cancerous effects of CGs. In addition, evidence of species differences of a magnitude sufficient to explain the results of many studies called for reconsideration of earlier results.

Principal Findings: In this report we identified primary B-precursor and T-ALL cells as being particularly susceptible to the cytotoxic effects of CGs. Digitoxin appeared most potent and IC(50) values for several patient samples were at concentrations that may be achieved in the clinic. Significant protein synthesis inhibition at concentrations corresponding to IC(50) was demonstrated in colorectal tumour cell lines moderately resistant to the cytotoxic effects of digoxin and digitoxin, but not in highly sensitive leukaemia cell lines.

Conclusion: It is suggested that further investigation regarding CGs may be focused on diagnoses like T- and B-precursor ALL.

Citing Articles

Ocular safety of repeated intravitreal injections of Carboplatin and Digoxin: A preclinical study on the healthy rabbits.

Khodabande A, Ghassemi F, Amoli F, Riazi-Esfahani H, Mahmoudzadeh R, Mehrpour M Pharmacol Res Perspect. 2021; 9(4):e00814.

PMID: 34250764 PMC: 8273607. DOI: 10.1002/prp2.814.

Anticancer and Antiviral Properties of Cardiac Glycosides: A Review to Explore the Mechanism of Actions.

Reddy D, Kumavath R, Barh D, Azevedo V, Ghosh P Molecules. 2020; 25(16).

PMID: 32784680 PMC: 7465415. DOI: 10.3390/molecules25163596.

Leukemic stem cell signatures identify novel therapeutics targeting acute myeloid leukemia.

Laverdiere I, Boileau M, Neumann A, Frison H, Mitchell A, Ng S Blood Cancer J. 2018; 8(6):52.

PMID: 29921955 PMC: 6889502. DOI: 10.1038/s41408-018-0087-2.

Proscillaridin A induces apoptosis and suppresses non-small-cell lung cancer tumor growth via calcium-induced DR4 upregulation.

Li R, Fan X, Duan F, Jiang Z, Pan H, Luo L Cell Death Dis. 2018; 9(6):696.

PMID: 29899551 PMC: 5999972. DOI: 10.1038/s41419-018-0733-4.

The cardiac glycoside convallatoxin inhibits the growth of colorectal cancer cells in a p53-independent manner.

Anderson S, Barton C Mol Genet Metab Rep. 2017; 13:42-45.

PMID: 28819586 PMC: 5548364. DOI: 10.1016/j.ymgmr.2017.07.011.

References

Beck W, Mueller T, Tanzer L . Altered surface membrane glycoproteins in Vinca alkaloid-resistant human leukemic lymphoblasts. Cancer Res. 1979; 39(6 Pt 1):2070-6. View

Lopez-Lazaro M, Pastor N, Azrak S, Ayuso M, Cortes F, Austin C . Digitoxin, at concentrations commonly found in the plasma of cardiac patients, antagonizes etoposide and idarubicin activity in K562 leukemia cells. Leuk Res. 2006; 30(7):895-8. DOI: 10.1016/j.leukres.2005.11.005. View

Kawazoe N, Aiuchi T, Masuda Y, Nakajo S, Nakaya K . Induction of apoptosis by bufalin in human tumor cells is associated with a change of intracellular concentration of Na+ ions. J Biochem. 1999; 126(2):278-86. DOI: 10.1093/oxfordjournals.jbchem.a022446. View

GOLDIN A, Safa A . Digitalis and cancer. Lancet. 1984; 1(8386):1134. DOI: 10.1016/s0140-6736(84)92556-x. View

Weidemann H . Na/K-ATPase, endogenous digitalis like compounds and cancer development -- a hypothesis. Front Biosci. 2005; 10:2165-76. DOI: 10.2741/1688. View

Stenkvist B . Is digitalis a therapy for breast carcinoma?. Oncol Rep. 1999; 6(3):493-6. View

Nesher M, Shpolansky U, Rosen H, Lichtstein D . The digitalis-like steroid hormones: new mechanisms of action and biological significance. Life Sci. 2007; 80(23):2093-2107. DOI: 10.1016/j.lfs.2007.03.013. View

Larsson R, Kristensen J, Sandberg C, Nygren P . Laboratory determination of chemotherapeutic drug resistance in tumor cells from patients with leukemia, using a fluorometric microculture cytotoxicity assay (FMCA). Int J Cancer. 1992; 50(2):177-85. DOI: 10.1002/ijc.2910500204. View

Masuda Y, Kawazoe N, Nakajo S, Yoshida T, Kuroiwa Y, Nakaya K . Bufalin induces apoptosis and influences the expression of apoptosis-related genes in human leukemia cells. Leuk Res. 1995; 19(8):549-56. DOI: 10.1016/0145-2126(95)00031-i. View

10.

Harris D, Kenrick M, Pither R, Anson J, Jones D . Development of a high-volume in situ mRNA hybridization assay for the quantification of gene expression utilizing scintillating microplates. Anal Biochem. 1996; 243(2):249-56. DOI: 10.1006/abio.1996.0513. View

11.

Graves R, Davies R, Brophy G, OBeirne G, Cook N . Noninvasive, real-time method for the examination of thymidine uptake events--application of the method to V-79 cell synchrony studies. Anal Biochem. 1997; 248(2):251-7. DOI: 10.1006/abio.1997.2088. View

12.

Xie Z, Askari A . Na(+)/K(+)-ATPase as a signal transducer. Eur J Biochem. 2002; 269(10):2434-9. DOI: 10.1046/j.1432-1033.2002.02910.x. View

13.

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):1493-7. DOI: 10.1248/bpb.29.1493. View

14.

Bassan R, Gatta G, Tondini C, Willemze R . Adult acute lymphoblastic leukaemia. Crit Rev Oncol Hematol. 2004; 50(3):223-61. DOI: 10.1016/j.critrevonc.2003.11.003. View

15.

Mekhail T, Kaur H, Ganapathi R, Budd G, Elson P, Bukowski R . Phase 1 trial of Anvirzel in patients with refractory solid tumors. Invest New Drugs. 2006; 24(5):423-7. DOI: 10.1007/s10637-006-7772-x. View

16.

Ihenetu K, Qazzaz H, Crespo F, Fernandez-Botran R, Valdes Jr R . Digoxin-like immunoreactive factors induce apoptosis in human acute T-cell lymphoblastic leukemia. Clin Chem. 2007; 53(7):1315-22. DOI: 10.1373/clinchem.2006.082081. View

17.

Lindhagen E, Nygren P, Larsson R . The fluorometric microculture cytotoxicity assay. Nat Protoc. 2008; 3(8):1364-9. DOI: 10.1038/nprot.2008.114. View

18.

Naumovski L, Morgan R, Hecht F, Link M, Glader B, Smith S . Philadelphia chromosome-positive acute lymphoblastic leukemia cell lines without classical breakpoint cluster region rearrangement. Cancer Res. 1988; 48(10):2876-9. View

19.

Newman R, Yang P, Hittelman W, Lu T, Ho D, Ni D . Oleandrin-mediated oxidative stress in human melanoma cells. J Exp Ther Oncol. 2006; 5(3):167-81. View

20.

Perne A, Muellner M, Steinrueck M, Craig-Mueller N, Mayerhofer J, Schwarzinger I . Cardiac glycosides induce cell death in human cells by inhibiting general protein synthesis. PLoS One. 2009; 4(12):e8292. PMC: 2788214. DOI: 10.1371/journal.pone.0008292. View