Glucocorticoid Induced Apoptosis in Leukemia

  • Lou A. Smets
  • Gajja Salomons
  • Joop van den Berg
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 457)

Abstract

Lymphoid and leukemic cells are uniquely sensitive to the lytic actions of glucocorticoid hormones which activate a programmed cell death in these cells. The response to glucocorticoids is sensitive to modulations at each step of hormone action: cellular uptake, binding and activation of cytosolic receptors, nuclear translocation and transcriptional activity of the activated receptor and the expression levels of pro- and anti-apoptotic genes. This review, based mainly on our studies with leukemic cells in tissue culture and on clinical observations in childhood acute lymphoblastic leukemia, summarizes the potential impact of these checkpoints in the treatment of this disease. In addition, we will discuss interventions that may reverse resistance or promote sensitivity to apoptosis of leukemic cells by glucocorticoid hormones.

Keywords

Apoptosis Leukemia Resistance Bcl-2 Mitochondria Glucocorticoids 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gregory, C., and Milner, A. Regulation of cell survival in Burkitt lymphoma: implications from studies of apoptosis following cold-shock treatment. Int. J. Cancer 1994, 57, 419–426.PubMedCrossRefGoogle Scholar
  2. 2.
    Smets, L. Programmed cell death (apoptosis) and response to anti-cancer drugs. Anti-Cancer Drugs 1994, 5, 3–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Schinkel, A. The physiological function of drug-transporting P-glycoproteins. Seminars in Cancer Biology 1997, 8, 161–170.PubMedCrossRefGoogle Scholar
  4. 4.
    Kaspers, G., Pieters, R., Klumper, E., De Waal, F., and Veerman, A. Glucocorticoid resistance in childhood leukemia. Leukemia and Lymphoma 1994, 13, 187–201.PubMedCrossRefGoogle Scholar
  5. 5.
    Van den Berg, J., Smets, L., Hutchinson, K., Van Rooij, H., and Van den Elshout, M. High levels of non-activated receptors in glucocorticoid-sensitive S49wt mouse lymphoma cells incubated with dexamethasone. J. Steroid Biochem. Molec. Biol. 1994, 51, 33–40.PubMedCrossRefGoogle Scholar
  6. 6.
    Van den Berg, J., Smets, L., Van den Elshout, M, Van Geel, I., and Janssen, M. Temperature dependence of glucocorticoid binding in sensitive and refractory murine leukaemia cells. Leuk. Res. 1993, 17, 263–269.PubMedCrossRefGoogle Scholar
  7. 7.
    Dowd, D. and Miesfeld, R. Evidence that glucocorticoid-and cyclic AMP-induced apoptotic pathways share distal events. Mol. Cell Biol. 1992, 12, 3600–3608.PubMedGoogle Scholar
  8. 8.
    Smets, L., Salomons, G., Van Rooij, H., and Van den Berg, J. Involvement of the glucocorticoid receptor in stress-induced apoptosis of leukemic cells. Leukemia 1998, 12, 406–413.PubMedCrossRefGoogle Scholar
  9. 9.
    Harmon, J., Norman, M., Fowlkes, B., and Thompson, E. Dexamethasone induces irreversible G1 arrest and death of a human lymphoid cell line. J. Cell. Physiol. 1979, 98, 267–278.PubMedCrossRefGoogle Scholar
  10. 10.
    Smets, L., Bout, B., Brouwer, M., and Tulp, A. Cytotoxic effects of dexamethasone restricted to non-cycling, early G1-phase cells of L1210 leukemia. J. Cell Physiol. 1983, 116, 397–403.PubMedCrossRefGoogle Scholar
  11. 11.
    Smets, L. and Van den Berg, J. Bcl-2 expression and glucocorticoid-induced apoptosis of leukemic and lymphoma cells. Leukemia and Lymphoma 1996, 20, 199–205.PubMedCrossRefGoogle Scholar
  12. 12.
    Hardin, J. McLeod, S., Grigoriva, A., Chang, R., Barlogie, B., Xiao, H. and Epstein, J. Interleukin-6 prevents dexamethasone-induced myeloma cell death. Blood 1994, 84, 3063–3070.PubMedGoogle Scholar
  13. 13.
    Sachs, L., and Lotem, J. Control of programmed cell death in normal and leukemic cells: new implications for therapy. Blood 1993, 82, 15–21.PubMedGoogle Scholar
  14. 14.
    Smets, L., Slater, R., Van Wering, E., Van der Does-van den Berg, A., Hart, A., Veerman, A., and Kamps, W. DNA index and %S-phase cells determined in acute lymphoblastic leukemia of children: a report from studies ALL V, ALL VI and ALL VIII (1979–1991) of the Dutch Childhood Leukemia Study Group and The Netherlands Workgroup on Cancer Genetics and Cytogenetics. Med. Pediatr. Oncol. 1995, 25. 437–444.PubMedCrossRefGoogle Scholar
  15. 15.
    Clarke, A., Purdie, C., Harrison, D., Morris, R., Bird, C., Hooper, M., and Wyllie, A. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 1993, 362, 894–852.Google Scholar
  16. 16.
    Smets, L., van den Berg, J., Acton, D., Top, B., Van Rooij, H., and Verwijs-Janssen, M. BCL-2 expression and mitochondrial activity in leukemic cells with different sensitivity to glucocorticoid-induced apoptosis. Blood 1994, 84, 1613–1619.PubMedGoogle Scholar
  17. 17.
    Reed, J. Bcl-2 and the regulation of programmed cell death. J. Cell Biol. 1994, 124, 1–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Salomons, G., Brady, H., Verwijs-Janssen, M, Van den Berg, J., Hart, A., Van den Berg, H., Behrendt, H., Hählen, K., and Smets, L. The Baxa:Bcl-2 ratio modulates the response to dexamethasone in leukemic cells and is highly variable in childhood acute leukemia. Int. J. Cancer 1997, 71, 959–965.PubMedCrossRefGoogle Scholar
  19. 19.
    Salomons, G., Buitenhuis, C., Martinez Muñoz, C., Verwijs-Janssen, M., Behrendt, H., Zsiros, J., and Smets, L. Mutational analysis of bax and bcl-2 in childhood acute lymphoblastic leukemia. Int. J. Cancer 1998 179, 273–277.CrossRefGoogle Scholar
  20. 20.
    Brady, H., Salomons, G., Bobeldijk, R. and Berns, A. T cells from baxa transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA-darnage-induced cell death in the absence of p53. EMBO J. 1996, 15, 1221–1230.PubMedGoogle Scholar
  21. 21.
    Uckun, F., Yang, Z., Sather, H., Steinherz, P., Nachman, J., Bostrom, B., Crotty, L., Sarquis, M., Ek, O., Zeren, T., Tubergen, D., Reaman, G., and Gaynon, P. Cellular expression of antiapoptotic Bcl-2 oncoprotein in newly diagnosed childhood acute lymphoblastic leukemia: a children’s cancer group study. Blood 1997, 89, 2506–2509.Google Scholar
  22. 22.
    Coustan-Smith, E., Kitanaka, A, Pui, C., McNinch, L., Evans, W., Raimondi, S., Behm, F., Arico, M., and Campana, D. Clinical relevance of Bcl-2 over-expression in childhood acute lymphoblastic leukemia. Blood 1996, 87, 1140–1146.PubMedGoogle Scholar
  23. 23.
    Pietenpol, J., Papadopoulos, N, Markowitz, S., Willson, J., Kinzler, K., and Vogelstein, B. Paradoxical inhibition of solid-tumor cell growth by bcl2. Cancer Res. 1994, 54, 3714–3717.PubMedGoogle Scholar
  24. 24.
    Brady, H., Gil-Gomez, G., Kirberg, J., and Berns, A. Baxα perturbs T cell development and affects cell cycle entry of T cells. EMBO J. 1996, 15, 6991–7001.PubMedGoogle Scholar
  25. 25.
    Huang, D., O’Reilly, A., Strasser, A., and Cory, S. The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. EMBO J. 1997, 16, 4628–4638.PubMedCrossRefGoogle Scholar
  26. 26.
    Decaudin, D., Geley, S., Hirsch, T., Castedo, M., Marchetti, P., Macho, A., Kofler, R., and Kroemer, G. Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents. Cancer Res. 1997, 57, 62–67.PubMedGoogle Scholar
  27. 27.
    Van den Berg, J., Smets, L., and Van Rooij, H. Agonist-free transformation of the glucocorticoid receptor in human B-lymphoma cells. J. Steroid Biochem. Mol. Biol. 1996, 57, 239–249.PubMedCrossRefGoogle Scholar
  28. 28.
    Klumper, E. Thesis 1995, Free University, AmsterdamGoogle Scholar
  29. 29.
    Kaspers, G., Veerman, A., Pieters, R., Van Zantwijk, C. Smets, L., Van Wering, E., and Van der Does-Van den Berg, A. In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia. Blood 1997, 90, 2723–2729.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Lou A. Smets
    • 1
  • Gajja Salomons
    • 1
  • Joop van den Berg
    • 1
  1. 1.Department of Experimental TherapyThe Netherlands Cancer Institute/Antoni van Leeuwenhoek HuisAmsterdamThe Netherlands

Personalised recommendations