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August 2000, Volume 14, Number 8, Pages 1502-1508
Table of contents    Previous  Article  Next   [PDF]
Spotlight on Apoptosis
Cell death beyond apoptosis
M V Blagosklonny

Medicine Branch, National Cancer Institute, NIH, Bethesda, MD, USA

Correspondence to: M V Blagosklonny, Medicine Branch, Bldg 10, R 12N226, NIH, Bethesda, MD 20892, USA; Fax: 301 402 0172

Abstract

Though the term apoptosis was originated in pathology and developmental biology as an alternative to necrosis, the tissue necrosis with inflammation is irrelevant to cell culture conditions where apoptosis is mostly studied. Furthermore, no one single morphological feature is either necessary or sufficient to define apoptosis. The emerging biochemical definition, a cell death with caspase activation, allows the distinction of alternative forms of cell death. Thus, inhibition of caspases delays but does not prevent cell death. Slow cell death without caspase activation may nevertheless be associated with DNA fragmentation. Oncogenic Ras, Raf, and mitogen-activated kinases inhibit apoptosis by affecting the cytochrome C/caspase-9 pathway but may arrest growth and cause slow cell death with delayed DNA fragmentation. Such 'slow' cell death without caspase activation is often caused by chemotherapeutic drugs. Whether a cell will undergo apoptosis or slow death depends not only on a chemotherapeutic agent but also on the readiness of cellular caspases. Therefore, one can distinguish apoptosis-prone (eg leukemia) vs apoptosis-resistant cells. Cell susceptibilities to spontaneous, starvation-induced and drug-induced apoptosis are correlated and characterize an apoptosis-prone phenotype. Finally, distinction of slow cell death allows rephrasing of a question regarding the goal of cancer therapy: apoptosis vs slow cell death, or cancer cell-selectivity regardless of the mode of cell death. Leukemia (2000) 14, 1502-1508.

Keywords

apoptosis; leukemia; chemotherapy

Introduction

Until recently, deciding whether cell death in cell culture occurs through apoptosis or non-apoptosis (ie necrosis) has been reminiscent of the medieval debate regarding the number of angels that can fit on the head of a pin. Despite the description of apoptosis in vivo,1 a lack of a strict definition for apoptosis coupled with underfined alternatives to apoptosis often lead to controversy. As noted by Vaux,2 the absence of precise meaning for the terms used can lead to several mutually exclusive, but correct answers. Apoptosis has been commonly described but not defined from four different points of view: (1) 'Programmed' cell death (PCD), even though 'program' originally referred to the development of an organism.3 While, in developmental biology, PCD occurs through apoptosis, in cancer and cell biology, it has, ironically, been rephrased that apoptosis occurs through PCD. (2) Cell death which is non-necrotic, even though the term tissue necrosis is not applicable to cell culture, where apoptosis is mostly studied. The term apoptosis was originally used to distinguish a type of cell death without inflammatory tissue injury from necrotic cell death in multicellular organism.1 In vivo, due to a release of cytoplasmic constituents to intercellular space, necrosis triggers the inflammatory response in tissue often resulting in scar formation. In contrast, the remains of apoptotic cells are phagocytized by surrounding cells. The distinction of tissue necrosis from cell apoptosis is arbitrary because of the irrelevance of the pathological term 'tissue necrosis' to the cell culture. As a consequence, every type of cell death which did not fulfill arbitrary criteria of apoptosis were called necrosis. Moreover, 'necrosis' is used to refer to very different forms of cell death. At one extreme there is an ultra-rapid cell death. At the other end of the spectrum there is slow cell death: eg cell senescence was described as necrosis-like death or delayed necrosis.4 (3) A combination of morphological features (nuclear fragmentation, DNA degradation, cell shrinkage, membrane bledding, chromatin condensation), even though each of them are neither essential nor sufficient. This results in such terms as necrosis with apoptotic morphology or apoptosis with necrotic morphology.4 (4) An active process of dying that requires energy and de novo gene expression, even though inhibitors of transcription/translation often induce apoptosis or, at least, do not inhibit apoptosis.5,6,7,8,9

A dead cell is characterized by irreversible cessation of metabolism and inability to exclude substrates, for example, the inability to metabolize MTT and to exclude trypan blue. Apoptosis (as well as other forms of cell death) is a process of dying and until the cell is dead, it may exclude trypan blue or exhibit any other markers of a living cell.10 Therefore, using the common characteristics of a dead cell, one cannot distinguish apoptosis and other forms of cell death (eg necrosis).

Emerging definition for apoptosis: caspase-mediated cell death

A canonical example of apoptosis is a rapid death of Jurkat cells following exposure to FasL. The process is initiated on cellular membranes by recruiting caspase-8 to the cytosolic domain of ligated Fas.11,12 Caspases are cysteine proteases which cleave intracellular proteins including downstream caspases.13,14,15 Since the Fas-induced cell death requires pre-synthesized caspases, receptor to FasL and adaptor proteins, the process is genetically programmed but does not depend on protein synthesis. Most other apoptotic stimuli (including chemotherapeutic drugs) activate the 'mitochondrial' pathway which involves the activation of caspase-9 by mitochondrial products leading to caspase-3 activation.16 Caspase activation brings about DNA fragmentation and laddering due to the caspase-mediated activation of nucleases which cleave DNA into internucleosomal fragments.17,18,19,20,21 Also, cleavage of cytoskeletal proteins contributes to membrane bledding, nuclear breakdown, cell shrinkage and other morphological features22 and appearance of phosphatidylserine (PS) on the cell surface.23 Externalization of phosphatidylserine signals phagocytosis, and therefore caspase activation prevents tissue necrosis in vivo. Irreversible cleavage of key proteins ensures inevitable cessation of synthesis and metabolism: a cell death.

A definition of apoptosis is emerging as cell death associated with caspase activation or caspase-mediated cell death,24 although, as noticed by Vaux, the definition may be weakened by referring to apoptotic morphology.2 Simply, 'apoptotic morphology' should not appear in the definition. Cell death with caspase activation is sufficient and necessary for apoptosis whereas specific morphological changes can be considered as mere markers of caspase activation if they can be abolished by the inhibitors of caspases. This definition provides easily measurable markers such as PARP cleavage or externalization of phosphatidylserine. In contrast, as shown in Figure 1, DNA internucleosomal fragmentation may or may not be a consequence of caspase activation.25,26,27,28,29 DNA degradation is not required for apoptotic cell death,30 and, on the other hand, caspases are not required for endonuclease activation in the cell-free system.31 By definition, caspase activation without death32 is not apoptosis. In addition, the term 'apoptosis without caspase activation' contradicts the definition.

Alternative forms of cell death: apoptosis vs slow cell death

Inhibition of caspases often blocks cell shrinkage, externalization of phosphatidylserine, nuclear condensation, or DNA fragmentation, but the cells still eventually die.33,34 For example, zVAD-fmk, an inhibitor of the caspases, interferes with all the morphological and biochemical changes associated with apoptosis induced by DNA damaging drugs. Nonetheless, the insulted cells eventually die with cytoplasmic and nuclear vacuolization.34 In other cases, 'apoptotic' morphologies (shrinkage, membrane bledding and nuclear condensation) are not blocked by caspase inhibitors but the cells continue to die in a protractive and inefficient manner.35 Thus, inhibitors of caspases block apoptosis but cells may die of delayed 'necrosis', which I will refer to as slow cell death (Figure 1).

Slow cell death occurs if caspases are inhibited or absent. As the most obvious case, some cell lines are deficient in caspases, for example caspase-3,19,36 and therefore die by slow cell death. Non-apoptotic cell death without caspase activation may occur despite cytochrome C release.10 Even more important, slow cell death is a rule rather than an exception in fibroblast and most cancer cells, although it may be labelled as drug resistance.37 Furthermore, it has been shown that loss of interdigital cells in an embryo, a paradigm of cell death during development, may be non-apoptotic.30

Therefore, slow cell death is an alternative mode of cell death. What about necrosis? Is necrosis relevant to cell culture? As emphasized by Samali et al,24 there is a shift from apoptosis to necrosis with increasing concentration of a toxic compound. Often necrosis develops as ultra-fast cell death following particularly strong stimuli (Figure 2). Perhaps the term necrosis should be reserved for tissue necrosis in the animal or human organism and, at the very least, to ultra-fast cell death which develops before any caspase activation could occur (Figure 2).

Inhibition of apoptosis with induction of slow cell death

Regulators of apoptosis are not purely pro-apoptotic or anti-apoptotic. In the Bcl-2 family, Bcl-2 and BclxL are anti-apoptotic protein whereas Bax and BAD are pro-apoptotic.38 However, Bcl-2 may be apoptotic when grossly overexpressed,39 or converted from anti-apoptotic to apoptotic by Bcl-2 protein cleavage,40 which may accompany chemotherapy.41,42 In contrast, the low levels of p53 that otherwise is almost a symbol of apoptosis protect against apoptosis in some cell models.43

As is well known, oncogenes that stimulate proliferation can induce apoptosis.44 These pro-apoptotic oncogenes such as c-myc, E2F, cyclin D1, E1A activate downstream segments of growth stimulatory pathways. In contrast, 'upstream' oncogenes block apoptosis but may inhibit cell growth.45 The growth factor-dependent kinases (PI3-kinase, Raf kinases, MEK/MAPK) suppress apoptosis downstream of the release of cytochrome C from mitochondria.46,47 Phosphorylation of BAD is a common mechanism of anti-apoptotic activity.48 Bcr-Abl, a kinase activated in chronic myeloid leukemia, prevents the cytochrome C release thus delaying cell death in the Bcr-Abl positive K562 leukemia cells.49,50 Thus, anti-apoptotic oncogenes and kinases can prevent cytochrome C release and caspase-9 activation46,47,51 (Figure 3).

Remarkably, even these anti-apoptotic oncogenes may induce cell death.52 As an intriguing example, Ras plays a dual role in the cell death,53 that can be reconciled if one recognizes slow cell death as the alternative to apoptosis. Anti-apoptotic oncogenes can induce slow cell death. For example, in intestinal epithelial cells, apoptosis is suppressed by c-H-ras oncogene.54 Ras suppresses apoptosis by activating Raf-1/MAPK, P13 and other kinases46 (Figure 3). On the other hand, Ras may signal growth arrest due to induction of CDK inhibitors (see Ref. 45). Growth arrest can be associated with cell senescence.55 This eventually results in slow cell death (Figure 3). In fact, Ras induces cellular degeneration accompanied by cytoplasmic vacuoles, well-preserved nuclei in the absence of caspase activation,56 and protease inhibitors only marginally affected Ras-mediated cell death.57 Ras causes formation of giant multinucleated cells culminating in 'mitotic' death,58 the term which may be synonymous with slow cell death. Giant multinucleated cells were also observed in p21-associated slow cell death caused by proteasome inhibitors in MCF-7, an apoptosis-resistant cell line.59 Like Ras, Raf-1 suppresses apoptosis,60,61 but can induce slow cell death with DNA fragmentation in caspase-3-deficient MCF-7 cancer cells.62

In addition, phorbol ester (PMA), an activator of PKC/MAPK pathway, plays the dual role in cell death. In human Ras-expressing epithelial cells, PMA causes microscopic features of death (chromatin condensation, TdT labelling) and DNA fragmentation after a surprising lag of 4 days.63 This can be explained if it is considered that DNA fragmentation may be a sign of slow cell death, as well as that of apoptosis. While PMA did not cause caspase activation in HL60 cells,42 it causes DNA fragmentation and delayed slow cell death.64 Furthermore, PMA-induced differentiation blocks DNA fragmentation associated with apoptosis.6 Slow cell death is associated with PMA-induced growth arrest in SKBr3 breast cancer cells, whereas induction of proliferation in PMA-arrested cells by E1A converts death from slow to apoptotic.65 On the other hand, PMA prevents apoptosis caused by IL-3 withdrawal.66

Thus, Ras and MAPK inhibit apoptosis by affecting the cytochrome C/caspase-9 pathway but in some circumstances, may signal growth arrest due to the induction of CDK inhibitors (Figure 2). This growth arrest may lead to slow cell death, often called apoptosis on the basis of the delayed DNA fragmentation.

Proapoptotic drug- or apoptosis-prone cells

Like physiological stimuli and oncogenes, chemotherapy can induce either apoptosis or slow cell death which is also called the senescence-like phenotype.67 Although a drug concentration may determine the response,68,69 the choice between apoptosis and slow death significantly depends on a cell. Too easily, the ability of a chemotherapeutic agent to cause apoptosis in lymphoid or leukemic cells labels such drug as 'apoptotic', even though it does not necessarily induce apoptosis in other cells. As much as a drug may be potentially apoptotic, the cell may be apoptosis-prone. In brief, drugs induce apoptosis in apoptosis-prone cells.

Apoptosis-resistant phenotype is illustrated by the cross-resistance to different cytotoxic regimens in tumor cells because of failure of caspase-activation.70,71 A constitutive readiness of caspases confers the apoptosis-prone phenotype, whereas the downmodulation of caspase activities can enhance chemoresistance.72 It would be virtually impossible to find a cytotoxic agent that would not induce apoptosis in Jurkat leukemia cells and, to a lesser degree, HL-60 and U937 cells.9,73,74,75 In comparison with Jurkat and HL-60 cells, K562 CML cells are relatively resistant to apoptosis induced by a variety of stimuli, because the activation of caspase-3 is delayed or absent in K562 cells.49,50,76,77,78,79 Spontaneous apoptosis in leukemic cells in vitro correlated with drug sensitivity.80,81,82 Although leukemia cells are sensitive to apoptosis induced by serum starvation, epithelial cancer cells do not require serum for survival.81 Also, drug-resistant leukemic cells are resistant to serum starvation and differentiation-inducing agents.83 Thus, spontaneous apoptosis, growth factor starvation-induced apoptosis and drug-induced apoptosis are correlated characterizing the apoptosis-prone phenotype. Cowpox virus CrmA protein, a direct and specific inhibitor of caspase proteases prevented apoptosis in a leukemia cell line leading to delayed death and even cell recovery and repopulation.72 Furthermore, MCF-7 breast cancer cells lacking caspase-3 are resistant to apoptosis by numerous stimuli,25,84 but undergo growth arrest followed by slow cell death.78 Like MCF-7 cells, many other epithelial cancer cells die without caspase activation.10 Sensitivity to drug-induced cell death depends on intact apoptotic pathways leading to activation of caspases.85 Defects in the activation of the caspase-3 proteolytic system upon treatment with chemotherapeutic compounds is associated with resistance to apoptosis.86

Perhaps in epithelial cancer cell lines the frequency of apoptosis is overestimated. Usually DNA fragmentation or chromosome condensation is arbitrarily used to claim apoptosis in many studies, including my own. In contrast, caspase activation is rarely reported in cancer cells. However, DNA fragmentation could be caspase-independent.28,87 In addition, AIF causes chromatin condensation and large scale DNA fragmentation to fragments of approximately 50 kbp (see Ref. 88). Especially, high molecular weight DNA fragmentation is not specific to apoptosis.89 Furthermore, drugs or serum starvation can induce apoptosis without concomitant internucleosomal degradation of DNA.25,26,90 Such features as chromosome condensation are especially troublesome in apoptosis caused by microtubule-active drugs which cause chromosome condensation as a part of mitotic arrest. Even in leukemia, the cells with DNA breaks were identified in blood for up to 5 days following chemotherapy,91 that, in my opinion, is consistent with slow cell death.

A drug can induce apoptosis in some but not every cancer cell line, and I will provide examples of traditional and experimental therapeutics in order of increasing apoptotic potential. Glucocorticoids induce apoptosis in CLL (see Ref. 92), while they are not toxic to most non-lymphoid cells. In leukemia cell lines, microtubule-active drugs such as paclitaxel induce caspase activation culminating in cell death in 16-36 h,42,93 but many cancer cell lines undergo slow cell death for 3-6 days. Like microtubule active, DNA damaging drugs induce apoptosis in leukemia cells.41,94 DNA damaging drugs may induce slow cell death in cancer cells and fibroblasts.84,95 Experimental therapeutics, such as flavopiridol and UCN-01, induce apoptosis in leukemia cells,96,98 whereas some cancer cell lines including PC3 prostate cancer cell line are resistant.84,99,100,101 Nevertheless, flavopiridol induces DNA fragmentation in squamous cell carcinomas resistant to DNA-damaging drugs.102 Inhibitors of the proteasome induce apoptosis103,104,105 even in PC-3 cell line.106 Growth arrest without apoptosis was observed in caspase-3-deficient MCF-7 cells78 and such apoptosis-resistant cells as normal fibroblasts.107

Conclusions

With necrosis as an alternative to apoptosis, the statement 'apoptosis is a goal of cancer therapy' seems controversial. While apoptosis is utilized in the program of development of an organism to avoid the scar associated with necrosis, there is no goal to avoid tumor necrosis in cancer therapy. Chemotherapy may fail not because it causes tumor necrosis, but because it does not cause cell death. Despite the assumption that apoptosis is a response to DNA damage in order to prevent tumorigenesis, there is no evidence that apoptosis evolved by nature to fight against cancer. It is rather utilized in the development of an organism and in control of self-renewing tissues: leukocytes, lymphocytes, epithelium.108,109 Although the suppression in apoptosis contributes to carcinogenesis,44,110,111 self-renewing tissues are the main source of neoplasms. Therefore, apoptosis (as a goal of therapy) is an alternative to cancer cell survival.112,113,114 The discrimination of slow cell death from apoptosis allows rephrasing of the key question: is the goal of cancer therapy apoptosis or slow cell death. Although significance of apoptosis compared with replicative or slow death in cancer chemotherapy was not widely discussed, there are indications that apoptosis may be a desirable goal. There are better results in chemotherapy of apoptosis-prone tumors,95,111 and the lack of apoptosis correlated with failure to achieve complete remission.115 Leukemia cells readily undergo apoptosis, and leukemias are more susceptible to chemotherapy than most solid cancers.95,116,117,118 Even if a cell cannot undergo apoptosis, it can still die by slow death. Perhaps selectivity in killing cancer cells without killing normal cells is as important a goal of cancer therapy as is the mode of death taken by the cancer cell. Pardee and James119 demonstrated a selective protection of normal cells, utilizing a restriction point by normal but not cancer cells.120 Recent advances in oncogenes and signal transduction studies allow the exploitation of more detailed differences to protect normal cells. Thus, pharmacological inactivation of wt p53 may protect cells from the cytotoxic doses of DNA damaging drugs,121 whereas induction of wt p53 by low cytostatic doses allows the protection of these cells but not p53-deficient cancer cells from paclitaxel and vinblastine.122 Furthermore, a selective protection of normal cells may be achieved exploiting an adverse feature such as multidrug resistance, which is otherwise an obstacle for treatment.123

References

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, MEDLINE

2 Vaux DL. Caspases and apoptosis - biology and terminology. Cell Death Differ 1999; 6: 493-494, MEDLINE

3 Saunders JJW. Death in embryonic systems. Science 1966; 154: 604-612, MEDLINE

4 Kitanaka C. Kuchino Y. Caspase-independent programmed cell death with necrotic morphology. Cell Death Differ 1999; 6: 508-515, MEDLINE

5 Martin SJ. Protein or RNA synthesis inhibition induces apoptosis of mature human CD4+ T cell blasts. Immunol Lett 1993; 35: 125-134, MEDLINE

6 Solary E, Bertrand R, Kohn KW, Pommier Y. Differential induction of apoptosis in undifferentiated and differentiated HL-60 cells by DNA topoisomerase I and II inhibitors. Blood 1993; 81: 1359-1368, MEDLINE

7 Borner MM, Myers CE, Sartor O, Sei Y, Toko T, Trepel JB, Schneider E. Drug-induced apoptosis is not necessarily dependent on macromolecular synthesis or proliferation in the p53-negative human prostate cancer cell line PC-3. Cancer Res 1995; 55: 2122-2128, MEDLINE

8 Weil M, Jacobson MD, Coles HSR, Davies TJ, Gardner RL, Raff KD, Raff MC. Constitutive expression of the machinery for programmed cell death. J Cell Biol 1996; 133: 1053-1059, MEDLINE

9 Wesselborg S, Engels IH, Rossmann E, Los M, Schulze-Osthoff K. Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction. Blood 1999; 93: 3053-3063, MEDLINE

10 Li YZ, Li CJ, Pinto AV, Pardee AB. Release of mitochondrial cytochrome C in both apoptosis and necrosis induced by beta-lapachone in human carcinoma cells. Mol Med 1999; 5: 232-239, MEDLINE

11 Nagata S. Apoptosis by death factor. Cell 1997; 88: 355-365, MEDLINE

12 Ashkenasi A, Dixit VM. Death receptors: signaling and modulation. Science 1998; 281: 1305-1308, Article MEDLINE

13 Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998; 281: 1312-1316, Article MEDLINE

14 Green DR. Apoptotic pathways: the roads to ruin. Cell 1998; 94: 695-698, MEDLINE

15 Kumar S. Mechanisms mediating caspase activation in cell death. Cell Death Differ 1999; 6: 1060-1066, MEDLINE

16 Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309-1312, MEDLINE

17 Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC. Cleavage of poly(ADP-ribose)polymerase by a proteinase with properties like ICE. Nature 1994; 371: 346-347, MEDLINE

18 Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 1997; 89: 175-184, MEDLINE

19 Janicke RU, Sprengart ML, Wati MR, Porter AG. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 1998; 273: 9357-9360, Article MEDLINE

20 Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998; 391: 43-50, Article MEDLINE

21 McIlroy D, Sakahira H, Talanian RV, Nagata S. Involvement of caspase 3-activated DNase in internucleosomal DNA cleavage induced by diverse apoptotic stimuli. Oncogene 1999; 18: 4401-4408, MEDLINE

22 Mills JC, Stone NL, Pittman RN. Extranuclear apoptosis: the role of the cytoplasm in the execution phase. J Cell Biol 1999; 146: 703-707, MEDLINE

23 Martin SJ, Finucance DM, Amarante-Mendes GP, O'Brien GA, Green DR. Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity. J Biol Chem 1996; 271: 28753-28756, MEDLINE

24 Samali A, Zhivotovsky B, Jones D, Nagata S, Orrenius S. Apoptosis: cell death defined by caspase activation. Cell Death Differ 1999; 6: 495-496, MEDLINE

25 Oberhammer F, Wilson JW, Dive C, Morris ID, Hickman JA, Wakeling AE, Walker PR, Sikorska M. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J 1993; 12: 3679-3684, MEDLINE

26 Ormerod MG, Oneill CF, Robertson D, Harrap KR. Cisplatin induces apoposis in a human ovarian-carcinoma cell-line without concomitant internucleosomal degradation of DNA. Exp Cell Res 1994; 211: 231-237, MEDLINE

27 Rasola A, Farahi Far D, Hofman P, Rossi B. Lack of internucleosomal DNA fragmentation is related to Cl(-) efflux impairment in hematopoietic cell apoptosis. FASEB J 1999; 13: 1711-1723, MEDLINE

28 Dong Z, Saikumar P, Weinberg JM, Venkatachalam MA. Internucleosomal DNA cleavage triggered by plasma membrane damage during necrotic cell death. Involvement of serine but not cystein proteases. Am J Pathol 1997; 151: 1205-1213, MEDLINE

29 Khodarev NN, Sokolova IA, Vaughan AT. Mechanisms of induction of apoptotic DNA fragmentation. Int J Radiat Biol 1998; 73: 455-467, Article MEDLINE

30 Chautan M, Chazal G, Cecconi F, Gruss P, Golstein P. Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr Biol 1999; 9: 967-970, Article MEDLINE

31 Shimizu T, Pommier Y. Camptothecin-induced apoptosis in p53-null human leukemia HL60 cells and their isolated nuclei: effects of the protease inhibitors Z-VAD-fmk and dichloroisocoumarin suggest an involvement of both caspases and serine proteases. Leukemia 1997; 11: 1238-1244, MEDLINE

32 Zeuner A, Eramo A, Peschle C, De Maria R. Caspase activation without death. Cell Death Differ 1999; 6: 1075-1080, MEDLINE

33 Hirsch T, Marchetti P, Susin SA, Dallaporta B, Zamzami N, Marzo I, Geuskens M, Kroemer G. The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial premeability transition determine the mode of cell death. Oncogene 1997; 15: 1573-1581, MEDLINE

34 Amarante-Mendes GP, Finucane DM, Martin SJ, Cotter TG, Salvesen GS, Green DR. Anti-apoptotic oncogenes prevent caspase-dependent and independent commitment for cell death. Cell Death Differ 1998; 5: 298-306, MEDLINE

35 Borner C, Monney L. Apoptosis without caspases: an inefficient molecular guillotine. Cell Death Differ 1999; 6: 497-507, MEDLINE

36 Kolenko V, Uzzo RG, Bukowski R, Bander NH, Novick AC, Hsi ED, Finke JH. Dead or dying: necrosis vs apoptosis in caspase-deficient human renal cell carcinoma. Cancer Res 1999; 59: 2838-2842, MEDLINE

37 Houghton JA. Apoptosis and drug response. Curr Opin Oncol 1999; 11: 475-481, Article MEDLINE

38 Reed JC. Double identity for proteins of the Bcl-2 family. Nature 1997; 387: 773-776, Article MEDLINE

39 Shinoura N, Yoshida Y, Nishimura M, Muramatsu Y, Asai A, Kirino T, Hamada H. Expression level of Bcl-2 determines anti- or proapoptotic function. Cancer Res 1999; 59: 4119-4128, MEDLINE

40 Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, Ueno K, Hardwick JM. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 1997; 278: 1966-1968, Article MEDLINE

41 Fadeel B, Hassan Z, Hellstrom-Lindberg M, Henter J-I, Orrenius S, Zhivotovsky B. Cleavage of bcl-2 is an early event in chemotherapy-induced apoptosis of human myeloid leukemia cells. Leukemia 1999; 13: 719-728, MEDLINE

42 Blagosklonny MV, Chuman Y, Bergan RC, Fojo T. Mitogen-activated protein kinase pathway is dispensible for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells. Leukemia 1999; 13: 1028-1036, MEDLINE

43 Lassus P, Ferlin M, Piette J, Hibner U. Anti-apoptotic activity of low levels of wild-type p53. EMBO J 1996; 15: 4566-4573, MEDLINE

44 Evan G, Littlewood T. A matter of life and cell death. Science 1998; 281: 1317-1322, Article MEDLINE

45 Blagosklonny MV. A node between proliferation, apoptosis, and growth arrest. Bioessays 1999; 21: 704-709, Article MEDLINE

46 Kauffman-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G. Suppression of c-myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 1997; 385: 544-548, MEDLINE

47 Erhardt P, Schremser EJ, Cooper GM. B-Raf inhibits programmed cell death downstream of cytochrome c release from mitochondria by activating the MEK/Erk pathway. Mol Cell Biol 1999; 19: 5308-5315, MEDLINE

48 Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999; 286: 1358-1362, Article MEDLINE

49 Dubrez L, Eymin B, Sordet O, Droin N, Turhan AG, Solary E. BCR-ABL delays apoptosis upstream of procaspase-3 activation. Blood 1998; 91: 2415-2422, MEDLINE

50 Amarante-Mendes GP, Naekyung Kim C, Liu L, Huang Y, Perkins CL, Green DR, Bhalla K. Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3. Blood 1998; 91: 1700-1705, MEDLINE

51 Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282: 1318-1321, Article MEDLINE

52 Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 1998; 12: 2997-3007, MEDLINE

53 Arber N. Janus faces of ras: anti or pro-apoptotic? Apoptosis 1999; 4: 383-388,

54 Rak J, Mitsuhashi Y, Erdos V, Huang SN, Filmus J, Kerbel RS. Massive programmed cell death in intestinal epithelial cells induced by three-dimensional growth conditions: suppression by mutant c-H-ras oncogene expression. J Cell Biol 1995; 131: 1587-1598, MEDLINE

55 Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88: 593-602, Article MEDLINE

56 Chi S, Kitanaka C, Noguchi K, Mochizuki T, Nagashima Y, Shirouzu M, Fujita H, Yoshida M, Chen W, Asai A, Himeno M, Yokoyama S, Kuchino Y. Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells. Oncogene 1999; 18: 2281-2290, MEDLINE

57 Chen CY, Liou J, Forman LW, Faller DV. Differential regulation of discrete apoptotic pathways by Ras. J Biol Chem 1998; 273: 16700-16709, MEDLINE

58 Miranda EI, Santana C, Rojas E, Hernandez S, Ostrosky-Wegman P, Garcia-Carranca A. Induced mitotic death of HeLa cells by abnormal expression of c-H-ras. Mutat Res 1996; 349: 173-182, MEDLINE

59 Blagosklonny MV, Wu GS, Omura S, El-Deiry WS. Proteasome-dependent regulation of p21WAF1/CIP1 expression. Biochem Biophys Res Comm 1996; 227: 564-569, MEDLINE

60 Canman CE, Gilmer TM, Coutts SB, Kastan MB. Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev 1995; 9: 600-611, MEDLINE

61 McCubrey JA, Steelman LS, Hoyle PE, Blalock WL, Weinstein-Oppenheimer C, Franklin RA, Cherwinski H, Bosch E, McMahon M. Differential abilities of activated Raf oncoproteins to abrogate cytokine dependency, prevent apoptosis and induce autocrine growth factor synthesis in human hematopoietic cells. Leukemia 1998; 12: 1903-1929, MEDLINE

62 El-Ashry D, Miller DL, Kharbanda S, Lippman ME, Kern FG. Constitutive Raf-1 kinase activity in breast cancer cells induces both estrogen-independent growth and apoptosis. Oncogene 1997; 15: 423-435, MEDLINE

63 Hall-Jackson CA, Jones T, Eccles NG, Dawson TP, Bond JA, Gescher A, Wynford-Thomas D. Induction of cell death by stimulation of protein kinase C in human epithelial cells expressing a mutant ras oncogene: a potential therapeutic target. Br J Cancer 1998; 78: 641-651, MEDLINE

64 Solary E, Bertrand R, Pommier Y. Apoptosis of human leukemic HL-60 cells induced to differentiate by phorbol ester treatment. Leukemia 1994; 8: 792-797, MEDLINE

65 Blagosklonny MV. The mitogen-activated protein kinase pathway mediates growth arrest or E1A-dependent apoptosis in SKBr3 human breast cancer cells. Int J Cancer 1998; 78: 511-517, Article MEDLINE

66 McCubrey JA, Steelman LS, Sandlin G, Riddle RS, Ways DK. Effects of phorbol esters on an interleukin-3-dependent cell line. Blood 1990; 76: 63-72, MEDLINE

67 Chang B-D, Xuan Y, Broude EV, Zhu H, Schott B, Fang J, Roninson IB. Role of p53 and p21 waf1/cip1 in senescence-like terminal proliferation arrest induced in human cells by chemotherapeutic drugs. Oncogene 1999; 18: 4808-4818, MEDLINE

68 Chang B-D, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y, Kandel ES, Lausch E, Christov K, Roninson IB. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer drugs. Cancer Res 1999; 59: 3761-3767, MEDLINE

69 Kravtsov VD, Greer JP, Whitlock JA, Koury MJ. Use of the microculture kinetic assay of apoptosis to determine chemosensitivities of leukemias. Blood 1998; 92: 968-980, MEDLINE

70 Classen CF, Fulda S, Friesen C, Debatin KM. Decreased sensitivity of drug-resistant cells towards T cell cytotoxicity. Leukemia 1999; 13: 410-418, MEDLINE

71 Friesen C, Fulda S, Debatin KM. Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells. Leukemia 1997; 11: 1833-1841, MEDLINE

72 Antoku K, Liu Z, Johnson DE. Inhibition of caspase proteases by CrmA enhances the resistance of human leukemic cells to multiple chemotherapeutic agents. Leukemia 1997; 11: 1665-1672, MEDLINE

73 Bullock G, Ray S, Reed JC, Krajewski S, Ibrado AM, Huang Y, Bhalla K. Intracellular metabolism of Ara-C and resulting DNA fragmentation and apoptosis of human AML HL-60 cells possessing disparate levels of Bcl-2 protein. Leukemia 1996; 10: 1731-1740, MEDLINE

74 Turnbull KJ, Brown BL, Dobson PR. Caspase-3-like activity is necessary but not sufficient for daunorubicin-induced apoptosis in Jurkat human lymphoblastic leukemia cells. Leukemia 1999; 13: 1056-1061, MEDLINE

75 Kawabata Y, Hirokawa M, Kitabayashi A, Horiuchi T, Kuroki J, Miura AB. Defective apoptotic signal transduction pathway downstream of caspase-3 in human B-lymphoma cells: a novel mechanism of nuclear resistance. Blood 1999; 94: 3523-3530, MEDLINE

76 Roberts JR, Allison DC, Donehower RC, Rowinsky EK. Development of polyploidization in taxol resistant human leukemia cells in vitro. Cancer Res 1990; 50: 710-716, MEDLINE

77 Martins LM, Mesner PW, Kottke Tj, Basi GS, Sinha S, Tung JS, Svingen PA, Madden BJ, Takahashi A, McCormick DJ, Earnshaw WC, Kaufmann SH. Comparison of caspase activation and subcellular localization in HL-60 and K562 cells undergoing etoposide-induced apoptosis. Blood 1997; 90: 4283-4296, MEDLINE

78 An WG, Hwang SG, Trepel JB, Blagosklonny MV. Protease inhibitor-induced apoptosis: accumulation wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia 2000; 14: 1276-1283, MEDLINE

79 Smith BD, Bambach BJ, Vala MS, Barber JP, Enger C, Brodsky RA, Burke PJ, Gore SD, Jones RJ. Inhibited apoptosis and drug resistance in acute myeloid leukaemia. Br J Haematol 1998; 102: 1042-1049, MEDLINE

80 Efferth T, Fabry U, Osieka R. Apoptosis and resistance to daunorubicin in human leukemic cells. Leukemia 1997; 11: 1180-1186, MEDLINE

81 Blagosklonny MV, Somasundaram K, Wu GS, El-Deiry WS. Wild-type p53 is not sufficient for serum starvation-induced apoptosis in cancer cells but accelerates apoptosis in sensitive cells. Int J Oncol 1997; 11: 1165-1170,

82 Wuchter C, Karawajew L, Ruppert V, Buchner T, Schoch C, Haferlach T, Ratei R, Dorken B, Ludwig WD. Clinical significance of CD95, Bcl-2 and Bax expression and CD95 function in adult de novo acute myeloid leukemia in context of P-glycoprotein function, maturation stage, and cytogenetics. Leukemia 1999; 13: 1943-1953, MEDLINE

83 Kakihara T, Fukuda T, Kamishima T, Naito M, Tanaka A, Uchiyama M, Kishi K. Resistance to apoptosis induced by serum depletion and all-trans retinoic acid in drug-resistant leukemic cell lines. Leuk Lymphoma 1997; 26: 369-376, MEDLINE

84 Nieves-Neira W, Pommier Y. Apoptotic response to camptothecin and 7-hydroxystaurosporine (UCN-01) in the 8 human breast cancer cell lines of the NCI Anticancer Drug Screen: multifactorial relationships with topoisomerase I, protein kinase C, Bcl-2, p53, MDM-2 and caspase pathways. Int J Cancer 1999; 82: 396-404, MEDLINE

85 Los M, Herr I, Friesen C, Fulda S, Schulze-Osthoff K, Debatin KM. Cross-resistance of CD95- and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 proteases). Blood 1997; 90: 3118-3129, MEDLINE

86 Meinhardt G, Roth J, Totok G, Auner H, Emmerich B, Hass R. Signaling defect in the activation of caspase-3 and PKCdelta in human TUR leukemia cells is associated with resistance to apoptosis. Exp Cell Res 1999; 247: 534-542, MEDLINE

87 Sane AT, Bertrand R. Distinct steps in DNA fragmentation pathway during camptothecin-induced apoptosis involved caspase-, benzyloxycarbonyl- and N-tosyl-L-phenylalanylchloromethyl ketone-sensitive activities. Cancer Res 1998; 58: 3066-3072, MEDLINE

88 Lorenzo HK, Susin SA, Penninger J, Kroemer G. Apoptosis inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death. Cell Death Differ 1999; 6: 516-524, MEDLINE

89 Kataoka A, Kubota M, Wakazono Y, Okuda A, Bessho R, Lin YW, Usami I, Akiyama Y, Furusho K. Association of high-molecular-weight DNA fragmentation with apoptotic or non-apoptotic cell-death induced by calcium ionophore. FEBS Lett 1995; 364: 264-267, MEDLINE

90 Simm A, Bertsch G, Frank H, Zimmermann U, Hoppe J. Cell death of AKR-2B fibroblasts after serum removal: a process between apoptosis and necrosis. J Cell Sci 1997; 110: 819-828, MEDLINE

91 Gorczyca W, Bigman K, Mittelman A, Ahmed T, Gong JP, Melamed MR, Darzynkiewicz Z. Induction of DNA strand breaks associated with apoptosis during treatment of leukemias. Leukemia 1993; 7: 659-670, MEDLINE

92 Stoetzer OJ, Pogrebniak A, Scholz M, Pelka-Fleischer R, Gullis E, Darsow M, Nussler V, Wilmanns W. Drug-induced apoptosis in chronic lymphocytic leukemia. Leukemia 1999; 13: 1873-1880, MEDLINE

93 Ibrado AM, Liu L, Bhalla K. Bcl-xL overexpression inhibits progression of molecular events leading to paclitaxel-induced apoptosis of human AML HL-60 cells. Cancer Res 1997; 57: 1109-1115, MEDLINE

94 Datta R, Banach D, Kojima H, Talanian RV, Alnemri ES, Wong WW, Kufe DW. Activation of the CPP32 protease in apoptosis induced by 1-b-D arabinofuranosylcytosine and other DNA-damaging agents. Blood 1996; 88: 1936-1943, MEDLINE

95 Fisher DE. Apoptosis in cancer therapy: crossing the threshold. Cell 1994; 78: 539-542, MEDLINE

96 Shao RG, Shimizu T, Pommier Y. 7-Hydroxystaurosporine (UCN-01) induces apoptosis in human colon carcinoma and leukemia cells independently of p53. Exp Cell Res 1997; 234: 388-397, Article MEDLINE

97 Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, Villalba L, Hill K, Steinberg SM, Figg WD, Tompkins A, Arbuck SG, Sausville EA. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol 1998; 16: 2986-2999, MEDLINE

98 Parker BW, Kaur G, Nieves-Neira W, Taimi M, Kohlhagen G, Shimizu T, Losiewicz MD, Pommier Y, Sausville EA, Senderowicz AM. Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood 1998; 91: 458-465, MEDLINE

99 Akiyama T, Yoshida T, Tsujita T, Shimizu M, Mizukami T, Okabe M, Akinaga S. G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1/WAF1/Sdi1 in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res 1997; 57: 1495-1501, MEDLINE

100 Sugiyama K, Akiyama T, Shimizu M, Tamaoki T, Courage C, Gescher A, Akinaga S. Decrease in susceptibility toward induction of apoptosis and alteration in G1 checkpoint function as determinants of resistance of human lung cancer cells against the antisignaling drug UCN-01 (7-hydroxystaurosporine). Cancer Res 1999; 59: 4406-4412, MEDLINE

101 Kruger EA, Blagosklonny MV, Dixon SC, Figg WD. UCN-01, a protein kinase C inhibitor, inhibits endothelial proliferation and angiogenic hypoxic response. Invas Metast 2000; 18: 209-218,

102 Patel V, Senderowicz AM, Pinto DJ, Igishi T, Raffeld M, Quintanilla-Martinez L, Ensley JF, Sausville EA, Gutkind JS. Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J Clin Invest 1998; 102: 1674-1681, MEDLINE

103 Drexler HC. Activation of the cell death program by inhibition of proteasome function. Proc Natl Acad Sci USA 1997; 94: 855-860, Article MEDLINE

104 Orlowski RZ. The role of the ubiquitin-proteasome pathway in apoptosis. Cell Death Differ 1999; 6: 303-313, MEDLINE

105 Chandra J, Niemer I, Gilbreath J, Kliche KO, Andreeff M, Freireich EJ, Keating M, McConkey DJ. Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. Blood 1998; 92: 4220-4229, MEDLINE

106 Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59: 2615-2622, MEDLINE

107 An B, Goldfarb RH, Siman R, Dou QP. Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ 1998; 5: 1062-1075, MEDLINE

108 Squier MK, Sehnert AJ, Cohen JJ. Apoptosis in leukocytes. J Leuk Biol 1995; 57: 2-10,

109 Metcalfe A, Streuli C. Epithelial apoptosis. Bioessays 1997; 19: 711-720, MEDLINE

110 Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol 1999; 17: 2941-2954, MEDLINE

111 Schmitt CA, Lowe SW. Apoptosis and therapy. J Pathol 1999; 187: 127-137, Article MEDLINE

112 Kastan MB, Canman CE, Leonard CJ. P53, cell cycle control and apoptosis: implications for cancer. Cancer Metast Rev 1995; 14: 3-15,

113 Darzynkiewicz Z. Apoptosis in antitumor strategies - modulation of cell-cycle or differentiation. J Cell Biochem 1995; 58: 151-159, MEDLINE

114 Fadeel B, Orrenius S, Zhivotovsky B. Apoptosis in human disease: a new skin for the old ceremony. Biochem Biophys Res Commun 1999; 266: 699-717, MEDLINE

115 Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S, Wang HG, Zhang X, Bullrich F, Croce CM, Rai K, Hines J, Reed JC. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998; 91: 3379-3389, MEDLINE

116 Hannun YA. Apoptosis and the dilemma of cancer chemotherapy. Blood 1997; 89: 1845-1853, MEDLINE

117 Martin SJ, Green DR. Apoptosis as a goal of cancer therapy. Curr Opin Oncol 1994; 6: 616-621, MEDLINE

118 Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, Pandolfi PP, Warrell RPJ. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. New Engl J Med 1998; 339: 1341-1348, MEDLINE

119 Pardee AB, James LJ. Selective killing of transformed baby hamster kidney (BHK) cells. Proc Natl Acad Sci USA 1975; 72: 4994-4998, MEDLINE

120 Pardee AB. A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 1974; 71: 1286-1290, MEDLINE

121 Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV, Gudkov AV. A chemical inhibitor of p53 that protects mice from the side-effects of cancer therapy. Science 1999; 285: 1733-1737, Article MEDLINE

122 Blagosklonny MV, Robey R, Bates S, Fojo T. Pretreatment with DNA-damaging agents permits selective killing of checkpoint-deficient cells by microtubule-active drugs. J Clin Invest 2000; 105: 533-539, MEDLINE

123 Blagosklonny MV. Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal. Leukemia 1999; 13: 2031-2035, MEDLINE

Figures

Figure 1  Relationship between DNA fragmentation, apoptosis, and slow cell death. DNA fragmentation can occur during either apoptosis (cell death with caspase activation) or slow cell death without caspase activation.

Figure 2  Approximate time frame for 'necrosis', apoptosis, and slow cell death.

Figure 3  Inhibition of apoptosis but induction of slow cell death by Ras/Raf/MEK.

Received 29 February 2000; accepted 28 April 2000
August 2000, Volume 14, Number 8, Pages 1502-1508
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