Apoptosis: a distinctive form of cell death

  • L. B. Jordan
  • D. J. Harrison
Part of the Basic Science for the Cardiologist book series (BASC, volume 5)


As we have seen in the previous chapters, apoptosis is an evolutionary conserved process that is ubiquitous within the living multicellular organism, essential for function and development. In this chapter we aim to introduce the concept of necrosis to highlight the unique process of apoptosis, discuss the features of apoptosis and importantly discuss the difficulties in identifying programmed cell death.


Programme Cell Death Apoptotic Body Flow Cytometric Detection United Kingdom Introduction Chinese Hamster Ovary Cell Culture 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–257.PubMedGoogle Scholar
  2. 2.
    Trump BF, Berezesky IK, Chang SH, Phelps PC. The pathways of cell death: oncosis, apoptosis, and necrosis. Toxicologic Pathology. 1997;25:82–88.PubMedGoogle Scholar
  3. 3.
    Majno G, Joris I. Apoptosis, oncosis and necrosis. An overview of cell death. Am J Pathol. 1995;146:3–15.PubMedGoogle Scholar
  4. 4.
    Von Recklinghausen F. Untersuchungen uber Rachitis und Osteomalacie. Jena: Verlag Gustav Fischer; 1910.Google Scholar
  5. 5.
    Webb S J, Harrison DJ, Wyllie AH. In: Kaufmann SH, ed. Apoptosis: Pharmacological implications and therapeutic opportunities. London: Academic Press; 1997:1–34.Google Scholar
  6. 6.
    Freude B, Masters TN, Kostin S, Robicsek F, Schaper J. Cardiomyocyte apoptosis in acute and chronic conditions. Basic Res Cardiol. 1998;93:85–89.PubMedCrossRefGoogle Scholar
  7. 7.
    Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature, 1980;284:555–556.PubMedCrossRefGoogle Scholar
  8. 8.
    Columbano A. Cell death: current difficulties in discriminating apoptosis from necrosis in the context of pathological processes in vivo. J Cellular Biochemistry. 1995;58:181–190.CrossRefGoogle Scholar
  9. 9.
    Leist M, Nicotera P. The shape of cell death. Biochem Biophys Res Comm. 1997;236:1–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Jacobson MD, Burne JF, Raff MC. Programmed cell death and Bcl-2 protection in the absence of a nucleus, EMBO J. 1994; 13:1899–1910.PubMedGoogle Scholar
  11. 11.
    Schulze-Osthoff K, Walczak H, Droge W, Kramer PH, Cell nucleus and DNA fragmentation are not required for apoptosis. J Cell Biol. 1994;127: 15–20.PubMedCrossRefGoogle Scholar
  12. 12.
    Kaufmann SH. Induction of endonuclease DNA cleavage in human acute myelogenous leukaemia by etopiside, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res. 1989;49:5870–5878.PubMedGoogle Scholar
  13. 13.
    Ucker DS, Meyers J, Obermitter PS. Activation-driven T cell death. II. Quantitative differences alone distinguish stimuli triggering non-transformed T cell proliferation or death. J Immunol. 1992;149:1583–1592.PubMedGoogle Scholar
  14. 14.
    Lazebnik YA, Cole S, Cooke CA, Nelson WG, Earnshaw WC. Nuclear events of apoptosis in vitro in cell-free mitotic extracts: A model system for analysis of the active phase of apoptosis. J Cell Biol. 1993; 123:7–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Reipert S, Reipert BM, Hickman JA, Allen TD. Nuclear pore clustering is a consistent feature of apoptosis in vitro. Cell Death Differ. 1996;3:131–139.PubMedGoogle Scholar
  16. 16.
    Kroemer G, Petit P, Naofal Z, Vayssiere J-L, Mignotte B. The biochemistry of programmed cell death. FASEB J. 1995;9:1277–1287.PubMedGoogle Scholar
  17. 17.
    Fesus L, Thomazy V, Falus A, Induction and activation of tissue transaglutaminase during programmed cell death. FEBS Lett. 1987;224:104–108.PubMedCrossRefGoogle Scholar
  18. 18.
    Bursch W, Paffe S, Putz B, Barthei G, Schulte-Hermann R. Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats. Carcinogenesis. 1990;l1:847–853.CrossRefGoogle Scholar
  19. 19.
    Darzynkiewicz Z, Bedner E, Traganos F, Murakami T. Critical aspects in the analysis of apoptosis and necrosis. Human Cell. 1998;11:3–12.PubMedGoogle Scholar
  20. 20.
    Loo DT, Rillema JR. Measurement of cell death. Methods in Cell Biol. 1998;57:251–264.Google Scholar
  21. 21.
    Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labelling of nuclear DNA fragmentation. J Cell Biol. 1992; 119:493–501.PubMedCrossRefGoogle Scholar
  22. 22.
    Hotz MA, Gong J, Traganos F, Darzynkiewicz Z. Flow cytometric detection of apoptosis: comparison of the assays of in situ DNA degradation and chromatin changes. Cytometry. 1994;15:237–244.PubMedCrossRefGoogle Scholar
  23. 23.
    Moore AM, Donahue CJ, Bauer KD, Mather JP. Simultaneous measurement of cell cycle and apoptotic cell death. Methods in Cell Biol. 1998;57:265–278.Google Scholar
  24. 24.
    Li X, Traganos F, Melamed MR, Darynkiewicz Z. Simultaneous analysis of DNA replication and apoptosis during treatment of HL-60 cells with camptothecin and hyperthermia and mitogen stimulation of human lymphocytes. Cancer Res. 1994;54:4289–4293.PubMedGoogle Scholar
  25. 25.
    Li X, Traganos F, Melamed MR, Darynkiewicz Z. Single-step procedure for labelling DNA strand breaks with fluorescein-or BODIPY-conjugated deoxynucleotides detection of apoptosis and bromodeoxyuridine incorporation. Cytometry. 1995;20:172–180.PubMedCrossRefGoogle Scholar
  26. 26.
    Ansari B, Coates PJ, Greenstein BD, Hall PA. In situ end-labelling detects DNA strand breaks in apoptosis and other physiological and pathological states. J Pathol. 1993; 170:1–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Laio Y, Tang Z-Y, Liu K-D, Ye S-L, Huang Z. Apoptosis of human BEL-7402 hepatocellular carcinoma cells released by antisense H-RAS DNA-in vitro and in vivo studies, J Cancer Res Clin Oncol. 1997; 123:25–33.CrossRefGoogle Scholar
  28. 28.
    Zakeri ZF, Quaglino D, Latham T, Locksin RA. Delayed internucleosomal DNA fragmentation in programmed cell death. FASEB J. 1993;7:470–478.PubMedGoogle Scholar
  29. 29.
    Boe R, Gjersten BT, Vintermyr OK, Houge G, Lanotte M, Doskeland SO. The protein phosphatase inhibitor okadaic acid induces morphological changes of apoptosis in mammalian cells. Exp Cell Res. 1991;195:237–246.PubMedCrossRefGoogle Scholar
  30. 30.
    Oberhammer FA, Pavelka M, Sharma S, Tiefenbacher R, Purchio AF, Bursch W, Schulte-Hermann R. Induction of apoptosis in cultured hepatocytes and in regressing liver by growth factor beta 1. Proc Natl Acad Sci USA. 1992;89:5408–5412.PubMedCrossRefGoogle Scholar
  31. 31.
    Oberhammer FA, Bursch W, Parzefall W, Breit P, Erber E, Stadler M, Schulte HR. Effect of transforming growth factor beta on cell death of cultured rat hepatocytes. Cancer Res, 1991;51:2478–2485.PubMedGoogle Scholar
  32. 32.
    Cohen GM, Sun X-M, Snowden RT, Dinsdale D, Skilleter DN. Key morphological features of apoptosis may occur in the absence of internucleosomal DNA fragmentation. Biochem J. 1992;286:331–334.PubMedGoogle Scholar
  33. 33.
    Collins RJ, Harmon BV, Gobe GC, Kerr JFR. Internucleosomal DNA cleavage should not be the only criterion for identifying apoptosis. Int J Radiat Biol. 1992, 61:451–453.PubMedGoogle Scholar
  34. 34.
    Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled annexin V. J Immunol Methods. 1995; 184:39–51.PubMedCrossRefGoogle Scholar
  35. 35.
    Martin SJ, Reutelingsperger CPM, McGahon AJ, Rader JA, Vanschie ECAA, Laface DM, Green DR. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med. 1995;182:1545–1546.PubMedCrossRefGoogle Scholar
  36. 36.
    Boersma AWM, Nooter K, Oostrum RG, Stoter G. Quantification of apoptotic cells with fluorescein isothiocyanate-labelled annexin V in Chinese hamster ovary cell cultures treated with cisplatin. Cytometry. 1996;24:123–130.PubMedCrossRefGoogle Scholar
  37. 37.
    Bennet MR, Gibson DF, Schwartz SM, Tait JF. Binding and phagocytosis of apoptotic vascular smooth muscle is mediated in part by exposure of phosphatidylserine. Circul Res. 1995;77:1136–1142.Google Scholar
  38. 38.
    Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by APO-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996271:12687–12690.Google Scholar
  39. 39.
    Sallmann FR, Bourassa S, Saint-Cyr J, Poirier GG. Characterization of antibodies specific for the caspase cleavage site on poly(ADP-ribose) polymerase: specific detection of apoptotic fragments and mapping of the necrotic fragments of poly(ADP-ribose) polymerase. .Biochem Cell Biol. 1997;75:451–456.PubMedCrossRefGoogle Scholar
  40. 40.
    Clem RJ, Cheng EH, Karp CL, Kirsch DG, Ueno K, Takahashi A, Kastan MB, Griffin DG, Earnshaw WC, Veliuona MA, Hardwick JM. Modulation of cell death by Bcl-XL through caspase interaction. Proc NatlAcad Sci USA. 1998;95:554–559.CrossRefGoogle Scholar
  41. 41.
    Dive C, Gregory CD, Phipps DJ, Evans DL, Milner AE, Wyllie AH. Analysis and discrimination of necrosis and apoptosis (programmed cell death) by multiparameter flow cytometry. Biochim Biophys Acta 1992;1133:275–285.PubMedCrossRefGoogle Scholar
  42. 42.
    Deckers CLP, Lyons AB, Samuels K, Sanderson A, Maddy AH. Alternative pathways of apoptosis induced by methylprednisolone and valinomycin analyzed by flow cytometry. Exp Cell Res.1993;208:362–370.PubMedCrossRefGoogle Scholar
  43. 43.
    Ormerod MG, Sun X-M, Brown D, Snowden RT, Cohen GM. Quantification of apoptosis and necrosis by flow cytometry. Acta Oncol. 1993;32:417–424.PubMedGoogle Scholar
  44. 44.
    Nicoletti I, Migiorati G, Pagliacci MC, Grignani F, Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Meth.1991;139:271–279.CrossRefGoogle Scholar
  45. 45.
    Telford WG, King LE, Fraker PJ. Comparative evaluation of several DNA binding dyes in the detection of apoptosis-associated chromatin degradation by flow cytometry. Cytometry. 1992;13:137–143.PubMedCrossRefGoogle Scholar
  46. 46.
    Telford WG, King LE, Fraker PJ. Rapid quantification of apoptosis in pure and heterogeneous cell populations using flow cytometry. J Immunol Meth. 1994;172:1–16.CrossRefGoogle Scholar
  47. 47.
    Afanasyev VN, Korol AB, Matylevich NP, Pechatnikov VA, Umansky SR. The use of flow cytometry for the investigation of cell death. Cytometry. 1993; 14:603–609.PubMedCrossRefGoogle Scholar
  48. 48.
    Wroblewski F, LaDue JS. Lactate dehydrogenase activity in blood. Proc Soc Exp Biol Med. 1955;90:210–213.PubMedGoogle Scholar
  49. 49.
    Howie SEM, Sommerfield AJ, Gray E, Harrison DJ. Peripheral T lymphocyte depletion by apoptosis after CD4 ligation in vivo: selective loss of CD44-and ‘activating’ memory T cells. Clin Exp Immunol. 1994;95:195–200.PubMedGoogle Scholar
  50. 50.
    Savill J. Phagocyte recognition of apoptotic cells. Biochem Soc Trans. 1996;24:1065–1069.PubMedGoogle Scholar
  51. 51.
    Duvall E, Wyllie AH, Morris RG. Macrophage recognition of cells undergoing programmed cell death (apoptosis). Immunol. 1985;56:351–358.Google Scholar
  52. 52.
    Savill J. Apoptosis in resolution of inflammation. J Leukocyte Biol. 1997;61:375–380.PubMedGoogle Scholar
  53. 53.
    Savill JS, Dransfield I, Hogg N, Haslett C. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature. 1990;343:170–173.PubMedCrossRefGoogle Scholar
  54. 54.
    Savill JS, Hogg N, Ren Y, Haslett C. Thrombospondin co-operates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J Clin Invest, 1992;90:1513–1522.PubMedGoogle Scholar
  55. 55.
    Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 1992; 148:2207–2216.PubMedGoogle Scholar
  56. 56.
    Flora PK, Gregory CD. Recognition of apoptotic cells by human macrophage: inhibition of a monocyte/macrophage-specific monoclonal antibody. Eur J Immunol. 1994;24:2625.PubMedCrossRefGoogle Scholar
  57. 57.
    Ogasawara J, Waanabe-Fukunga R, Adachi M, Matsuzawa A, Kasgul T, Kitamura Y, Itoh N, Suda T, Nagata S. Lethal effect of the anti-Fas antibody in mice. Nature. 1993;364:806–809.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • L. B. Jordan
    • 1
  • D. J. Harrison
    • 1
  1. 1.University of EdinburghEdinburghUK

Personalised recommendations