, Volume 7, Issue 5, pp 407–412 | Cite as

Didemnin B induces apoptosis in proliferating but not resting peripheral blood mononuclear cells

  • M. A. Baker
  • D. R. Grubb
  • A. Lawen


We have previously shown that didemnin B, a branched cyclic depsipeptide composed of seven amino acids and two hydroxy acids, can induce rapid and complete apoptosis in HL-60 cells (Grubb, D.R. et al. (1995) Biochem. Biophys. Res. Commun. 215, 1130–1136). We now report that didemnin B can induce apoptosis in a wide range of transformed cell lines. Resting normal lymphocytes, however, are apparently unaffected by exposure to the drug. To investigate whether cell transformation, and/or cell proliferation is necessary for didemnin B to induce apoptosis, we examined the effect of didemnin B on freshly harvested human lymphocytes before and after stimulation with concanavalin A. Didemnin B induced apoptosis in normal lymphocytes only after mitogenic stimulation and therefore warrants further examination for its potential as a chemotherapeutic agent, especially for treatment of leukemia.

apoptosis cell proliferation chemotherapy concanavalin A didemnin B leukemia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Trump BF, Berezesky IK, Chang SH, Phelps PC The pathways of cell death: Oncosis, apoptosis, and necrosis. Toxicol Pathol 1997; 25: 82–88.Google Scholar
  2. 2.
    Bratton SB, MacFarlane M, Kelvin C, Cohen GM Protein complexes activate distinct caspase cascades in death receptor and stress-induced apoptosis. Exp Cell Res 2000; 256: 27–33.Google Scholar
  3. 3.
    Yin M, Oltvai ZN, Korsmeyer, SJ BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 1994; 369: 321–323.Google Scholar
  4. 4.
    Roth W, Wagenknecht B, Grimmel C, Dichgans J, Weller M Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: Association with Bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest. Br J Cancer 1998; 77: 404–411.Google Scholar
  5. 5.
    Zhang M, Raveche ES Apoptosis induction in fludarabine resistant malignant B-1 cells by G2-M cell cycle arrest. Oncol Rep 1998; 5: 23–30.Google Scholar
  6. 6.
    Zaffaroni N, Silvestrini R, Orlandi L, Bearzatto A, Gornati D, Villa R Induction of apoptosis by taxol and cisplatin and effect on cell cycle-related proteins in cisplatin-sensitive and-resistant human ovarian cells. Br J Cancer 1998; 77: 1378–1385.Google Scholar
  7. 7.
    Clary A, Larrue A, Pourquier P, Robert J Transcriptional downregulation of c-myc expression in an erythroleukemic cell line, K562, and its doxorubicin-resistant variant by two topoisomerase II inhibitors, doxorubicin and amsacrine. Anti-Cancer Drugs 1998; 9: 245–254.Google Scholar
  8. 8.
    Skladanowski A, Konopa J Adriamycin and daunomycin induce programmed cell death (apoptosis) in tumour cells. Biochem Pharmacol 1993; 46: 375–382.Google Scholar
  9. 9.
    Shin DM, Holoye PY, Forman A, et al Phase II clinical trial of didemnin B in previously treated small cell lung cancer. Invest New Drugs 1994; 12: 243–249.Google Scholar
  10. 10.
    Rinehart KL, Jr, Gloer JB, Hughes RG, Jr, et al Didemnins: Antiviral and antitumor depsipeptides from a caribbean tunicate. Science 1981; 212: 933–935.Google Scholar
  11. 11.
    Shen GK, Zukoski CF, Montgomery DW A specific binding site in Nb2 node lymphoma cells mediates the effects of didemnin B, an immunosuppressive cyclic peptide. Int J Immunopharmacol 1992; 14: 63–73.Google Scholar
  12. 12.
    Grubb DR, Wolvetang EJ, Lawen A Didemnin B induces cell death by apoptosis: The fastest induction of apoptosis ever described. Biochem Biophys Res Commun 1995; 215: 1130–1136.Google Scholar
  13. 13.
    Johnson KL, Grubb DR, Lawen A Unspecific activation of caspases during the induction of apoptosis by didemnin B in human cell lines. J Cell Biochem 1999; 72: 269–278.Google Scholar
  14. 14.
    Johnson KL, Vaillant F, Lawen A Protein tyrosine kinase inhibitors prevent didemnin B-induced apoptosis in HL-60 cells. FEBS Lett 1996; 383: 1–5.Google Scholar
  15. 15.
    Johnson KL, Lawen A Rapamycin inhibits didemnin B-induced apoptosis in human HL-60 cells: Evidence for the possible involvement of FK506-binding protein 25. Immunol Cell Biol 1999; 77: 242–248.Google Scholar
  16. 16.
    Grubb DR, Ly JD, Vaillant F, Johnson KL, Lawen A Mitochondrial cytochrome c release is caspase-dependent and does not involve mitochondiral permeability transition in didemnin B-induced apoptosis. Oncogene 2001; 20: 4085–4094.Google Scholar
  17. 17.
    Beidler DR, Ahuja D, Wicha MS, Toogood PL Inhibition of protein synthesis by didemnin B is not sufficient to induce apoptosis in human mammary carcinoma (MCF7) cells. Biochem Pharmacol 1999; 58: 1067–1074.Google Scholar
  18. 18.
    Crampton SL, Adams EG, Kuentzel SL, Li LH, Badiner G, Bhuyan BK Biochemical and cellular effects of didemnins A and B. Cancer Res 1984; 44: 1796–1801.Google Scholar
  19. 19.
    Jouin P, Poncet J, Dufour MN, et al Antineoplastic activity of didemnin congeners: Nordidemnin and modified chain analogues. J Med Chem 1991; 34: 486–491.Google Scholar
  20. 20.
    Pauli RM, Strauss BS Proliferation of human peripheral lymphocytes. Characteristics of cells once stimulated or restimulated by concanavalin A. Exp Cell Res 1973; 82: 357–366.Google Scholar
  21. 21.
    Antonsson B, Martinou J-C The Bcl-2 protein family. Exp Cell Res 2000; 256: 50–57.Google Scholar
  22. 22.
    Montgomery DW, Zukoski CF Didemnin B: A new immunosuppressive cyclic peptide with potent activity in vitro and in vivo. Transplantation 1985; 40: 49–56.Google Scholar
  23. 23.
    Hale AJ, Smith CA, Sutherland LC, et al Apoptosis: Molecular regulation of cell death. Eur J Biochem 1996; 236: 1–26.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • M. A. Baker
    • 1
  • D. R. Grubb
    • 1
  • A. Lawen
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, School of Biomedical SciencesMonash UniversityAustralia

Personalised recommendations