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. 1995 May;71(5):937–941. doi: 10.1038/bjc.1995.181

Induction of apoptosis by anti-cancer drugs with disparate modes of action: kinetics of cell death and changes in c-myc expression.

A C Wood 1, P Elvin 1, J A Hickman 1
PMCID: PMC2033809  PMID: 7734316

Abstract

Incubation of CCRF CEM C7A human lymphoblastic leukaemia cells with etoposide (VP16) or N-methylformamide (NMF) induced apoptotic cell death. The kinetics of onset of apoptosis was determined and compared with that for dexamethasone-treated cells. The drugs induced 50% apoptosis at different rates: etoposide by approximately 18 h, NMF by 40 h and dexamethasone (DEX) by 52 h. In each case, the onset of apoptosis above 10% was preceded by a delay period. This was 8 h for etoposide, between 8 and 12 h for NMF and 36 h for dexamethasone. When cells were incubated for 36 h with dexamethasone and the drug washed out, addition of NMF induced apoptosis without any delay, suggesting that certain common biochemical events are required to prime the cells for apoptosis. However, cells treated for 8 h with NMF did not undergo immediate apoptosis on the addition of DEX. Analysis of the cellular content of the c-myc protein showed this to be undetectable by 2, 6 and 12 h after treatment with etoposide, NMF and DEX respectively. The rapid onset of NMF-induced cell death after a 36 h DEX pretreatment occurred 24 h after the loss of expression of c-Myc protein, suggesting that the expression of c-myc is not required for drug-induced cell death. In contrast to DEX-induced apoptosis, concomitant incubation of cells with NMF or etoposide and 200 nM of the protein synthesis inhibitor cycloheximide did not inhibit apoptotic cell death. The idea that drugs with different modes of action initiate conserved responses which engage a programmed cell death is discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Askew D. S., Ashmun R. A., Simmons B. C., Cleveland J. L. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene. 1991 Oct;6(10):1915–1922. [PubMed] [Google Scholar]
  2. Bill C. A., Gescher A., Hickman J. A. Effects of N-methylformamide on the growth, cell cycle, and glutathione status of murine TLX5 lymphoma cells. Cancer Res. 1988 Jun 15;48(12):3389–3393. [PubMed] [Google Scholar]
  3. Caelles C., Helmberg A., Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature. 1994 Jul 21;370(6486):220–223. doi: 10.1038/370220a0. [DOI] [PubMed] [Google Scholar]
  4. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  5. Dibner M. D., Ireland K. A., Koerner L. A., Dexter D. L. Polar solvent-induced changes in membrane lipid lateral diffusion in human colon cancer cells. Cancer Res. 1985 Oct;45(10):4998–5003. [PubMed] [Google Scholar]
  6. Dive C., Hickman J. A. Drug-target interactions: only the first step in the commitment to a programmed cell death? Br J Cancer. 1991 Jul;64(1):192–196. doi: 10.1038/bjc.1991.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eastman A. Apoptosis: a product of programmed and unprogrammed cell death. Toxicol Appl Pharmacol. 1993 Jul;121(1):160–164. doi: 10.1006/taap.1993.1141. [DOI] [PubMed] [Google Scholar]
  8. Evan G. I., Lewis G. K., Ramsay G., Bishop J. M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. doi: 10.1128/mcb.5.12.3610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Evan G. I., Wyllie A. H., Gilbert C. S., Littlewood T. D., Land H., Brooks M., Waters C. M., Penn L. Z., Hancock D. C. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992 Apr 3;69(1):119–128. doi: 10.1016/0092-8674(92)90123-t. [DOI] [PubMed] [Google Scholar]
  10. Harmon J. M., Norman M. R., Fowlkes B. J., Thompson E. B. Dexamethasone induces irreversible G1 arrest and death of a human lymphoid cell line. J Cell Physiol. 1979 Feb;98(2):267–278. doi: 10.1002/jcp.1040980203. [DOI] [PubMed] [Google Scholar]
  11. Hickman J. A. Apoptosis induced by anticancer drugs. Cancer Metastasis Rev. 1992 Sep;11(2):121–139. doi: 10.1007/BF00048059. [DOI] [PubMed] [Google Scholar]
  12. Hickman J. A., Potten C. S., Merritt A. J., Fisher T. C. Apoptosis and cancer chemotherapy. Philos Trans R Soc Lond B Biol Sci. 1994 Aug 30;345(1313):319–325. doi: 10.1098/rstb.1994.0112. [DOI] [PubMed] [Google Scholar]
  13. Lachman H. M., Skoultchi A. I. Expression of c-myc changes during differentiation of mouse erythroleukaemia cells. Nature. 1984 Aug 16;310(5978):592–594. doi: 10.1038/310592a0. [DOI] [PubMed] [Google Scholar]
  14. Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
  15. Liu L. F. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem. 1989;58:351–375. doi: 10.1146/annurev.bi.58.070189.002031. [DOI] [PubMed] [Google Scholar]
  16. Mitchell L. S., Neill R. A., Birnie G. D. Temporal relationships between induced changes in c-myc mRNA abundance, proliferation, and differentiation in HL60 cells. Differentiation. 1992 Mar;49(2):119–125. doi: 10.1111/j.1432-0436.1992.tb00776.x. [DOI] [PubMed] [Google Scholar]
  17. Norman M. R., Thompson E. B. Characterization of a glucocorticoid-sensitive human lymphoid cell line. Cancer Res. 1977 Oct;37(10):3785–3791. [PubMed] [Google Scholar]
  18. Oberhammer F., Wilson J. W., Dive C., Morris I. D., Hickman J. A., Wakeling A. E., Walker P. R., Sikorska M. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J. 1993 Sep;12(9):3679–3684. doi: 10.1002/j.1460-2075.1993.tb06042.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sen S., D'Incalci M. Apoptosis. Biochemical events and relevance to cancer chemotherapy. FEBS Lett. 1992 Jul 27;307(1):122–127. doi: 10.1016/0014-5793(92)80914-3. [DOI] [PubMed] [Google Scholar]
  20. Thulasi R., Harbour D. V., Thompson E. B. Suppression of c-myc is a critical step in glucocorticoid-induced human leukemic cell lysis. J Biol Chem. 1993 Aug 25;268(24):18306–18312. [PubMed] [Google Scholar]
  21. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wood A. C., Waters C. M., Garner A., Hickman J. A. Changes in c-myc expression and the kinetics of dexamethasone-induced programmed cell death (apoptosis) in human lymphoid leukaemia cells. Br J Cancer. 1994 Apr;69(4):663–669. doi: 10.1038/bjc.1994.128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wyllie A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. doi: 10.1038/284555a0. [DOI] [PubMed] [Google Scholar]
  24. Yen A. Control of HL-60 myeloid differentiation. Evidence of uncoupled growth and differentiation control, S-phase specificity, and two-step regulation. Exp Cell Res. 1985 Jan;156(1):198–212. doi: 10.1016/0014-4827(85)90274-5. [DOI] [PubMed] [Google Scholar]
  25. Yuh Y. S., Thompson E. B. Glucocorticoid effect on oncogene/growth gene expression in human T lymphoblastic leukemic cell line CCRF-CEM. Specific c-myc mRNA suppression by dexamethasone. J Biol Chem. 1989 Jun 25;264(18):10904–10910. [PubMed] [Google Scholar]

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