Apoptosis: from Signalling Pathways to Therapeutic Tools

Document Type: Review Article


1 Department of Pharmacology and Pharmacological Research Centre of Medicinal Plants, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Immunology and Oncology Unit, Newcastle Mater Hospital, Newcastle, New South Wales, Australia


Apoptosis or programmed cell death is a gene regulated phenomenon which is important in both physiological and pathological conditions. It is characterized by distinct morphological features including chromatin condensation, cell and nuclear shrinkage, membrane blebbing and oligonucleosomal DNA fragmentation. Although, two major apoptotic pathways including 1) the death receptor (extrinsic) and 2) mitochondrial (intrinsic) pathway have been identified, recently endoplasmic reticulum and lysosomal pathways have been also recognized. Depending on both the cell type and the initiating factor, distinct pathways are activated. The pathways share a common final phase of apoptosis, consisting of activation of the executioner caspases and dismantling of substrates critical for cell survival. The important regulatory mechanisms include death receptors, caspases, mitochondria and Bcl-2 family proteins. Modulating of apoptosis is a novel therapeutic strategy in treatment of different diseases. These include situations with unwanted cell accumulation (cancer) and failure to diminish aberrant cells (autoimmune diseases) or diseases with an inappropriate cell loss (heart failure, stroke, AIDS and neurodegenerative diseases).  Modulation of apoptosis is a novel therapeutic strategy in treatment of different diseases. Many approaches including gene therapy, antisense strategies and numerous apoptotic drugs to target specific apoptotic regulators, are currently being developed. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, signaling as well as a discussion of apoptosis in diseases and effective therapy.


1.            Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-357.

2.            Kerr JFR. History of the events leading to the formulation of the apoptosis concept. Toxicology 2002; 181-182: 471-474.

3.            Paweletz N. Walther Flemming: Pioneer of mitosis research. Nat Rev Mol Cell Biol 2001; 2: 72-75.

4.            Debnath J, Baehrecke EH, Kroemer G. Does autophagy contribute to cell death? Autophagy 2005; 1: 66-74.

5.            Formigli L, Papucci L, Tani A, Schiavone N, Tempestini A, Orlandini GE, et al. Aponecrosis: Morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J Cell Physiol 2000; 182: 41-49.

6.            Sperandio S, De Belle I, Bredesen DE. An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA 2000; 97: 14376-14381.

7.            Elmore S.Apoptosis: A Review of Programmed Cell Death. Toxicol Pathol 2007; 35: 495-516.

8.            Steller H. Mechanisms and genes of cellular suicide. Science 1995; 267: 1445-1449.

9.            Williams GT, Smith CA. Molecular regulation of apoptosis: Genetic controls on cell death. Cell 1993; 74: 777-779.

10.          Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development. Cell 1997; 88: 347-354.

11.          Fleischer A, Ghadiri A, Dessauge F, Duhamel M, Rebollo MP, varez-Franco F, et al. Modulating apoptosis as a target for effective therapy. Mol Immunol 2006; 43: 1065-1079.

12.          Norbury CJ, Hickson ID. Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol 2001; 41: 367-401.

13.          Mousavi SH, Hersey P. Role of caspases and reactive oxygen species in rose bengal-induced toxicity in melanoma cells. Iran J Basic Med Sci 2007; 10: 210-215.

14.          Hacker G. The morphology of apoptosis. Cell Tissue Res 2000; 301: 5-17.

15.          Kurosaka K, Takahashi M, Watanabe N, Kobayashi Y. Silent Cleanup of Very Early Apoptotic Cells by Macrophages. J Immunol 2003; 171: 4672-4679.

16.          Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature 2000; 407: 784-788.

17.          Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407: 770-776.

18.          Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 1999; 15:269-290.

19.          Cohen GM. Caspases: The executioners of apoptosis. Biochem J 1997; 326: 1-16.

20.          Rai NK, Tripathi K, Sharma D, Shukla VK. Apoptosis: A basic physiologic process in wound healing. Int J Low Extrem Wounds 2005; 4: 138-144.

21.          Hu S, Snipas SJ, Vincenz C, Salvesen G, Dixit VM. Caspase-14 is a novel developmentally regulated protease. J Biol Chem 1998; 273: 29648-29653.

22.          Kang SJ, Wang S, Kuida K, Yuan J. Distinct downstream pathways of caspase-11 in regulating apoptosis and cytokine maturation during septic shock response. Cell Death Differ 2002; 9: 1115-1125.

23.          Koenig U, Eckhart L, Tschachler E. Evidence that caspase-13 is not a human but a bovine gene. Biochem Biophys Res Commun 2001; 285: 1150-1154.

24.          Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 2000; 403: 98-103.

25.          Nemes J, Friis RR, Aeschlimann D, Saurer S, Paulsson M, Fesus L. Expression and activation of tissue transglutaminase in apoptotic cells of involuting rodent mammary tissue. Eur J Cell Biol 1996; 70: 125-133.

26.          Bortner CD, Oldenburg NBE, Cidlowski JA. The role of DNA fragmentation in apoptosis. Trends Cell Biol 1995; 5: 21-26.

27.          Bratton DL, Fadok VA, Richter DA, Kailey JM, Guthrie LA, Henson PM. Appearance of phosphatidylserine on apoptotic cells requires calcium- mediated nonspecific flip-flop and is enhanced by loss of the aminophospholipid translocase. J Biol Chem 1997; 272: 26159-26165.

28.          Arur S, Uche UE, Rezaul K, Fong M, Scranton V, Cowan AE, et al. Annexin I is an endogenous ligand that mediates apoptotic cell engulfment. Dev Cell 2003; 4: 587-598.

29.          Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 2005; 123: 321-334.

30.          Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nature Med 2000; 6: 41-48.

31.          Hirsch T, Marchetti P, Susin SA, Dallaporta B, Zamzami N, Marzo I, et al. The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death. Oncogene 1997; 15: 1573-1581.

32.          Zeiss CJ. The apoptosis-necrosis continuum: Insights from genetically altered mice. Vet Pathol 2003; 40: 481-495.

33.          Levin S, Bucci TJ, Cohen SM, Fix AS, Hardisty JF, LeGrand EK, et al. The nomenclature of cell death: Recommendations of an ad hoc Committee of the Society of Toxicologic Pathologists. Toxicol Pathol 1999; 27: 484-490.

34.          Majno G, Joris I. Apoptosis, oncosis, and necrosis: An overview of cell death. Am J Pathol 1995; 146: 3-15.

35.          Trump BF, Berezesky IK, Chang SH, Phelps PC. The pathways of cell death: Oncosis, apoptosis, and necrosis. Toxicol Pathol 1997; 25: 82-88.

36.          Cotran RS, Kumar V, Robbins SL. Cellular injury and cellular death. Pathologic Basis of Disease 1994; 1-34.

37.          Fiers W, Beyaert R, Declercq W, Vandenabeele P. More than one way to die: Apoptosis, necrosis and reactive oxygen damage. Oncogene 1999; 18: 7719-7730.

38.          Denecker G, Vercammen D, Declercq W, Vandenabeele P. Apoptotic and necrotic cell death induced by death domain receptors.Cell Mol Life Sci 2001;58: 356-370

39.          Leist M, Single B, Castoldi AF, Hnle S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: A switch in the decision between apoptosis and necrosis. J Exp Med 1997; 185: 1481-1486.

40.          Broker LE, Kruyt FAE, Giaccone G. Cell death independent of caspases: A review. Clin Cancer Res 2005; 11: 3155-3162.

41.          Edinger AL, Thompson CB. Death by design: Apoptosis, necrosis and autophagy. Curr Opin Cell Biol 2004; 16:663-669.

42.          Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 2004; 18: 1272-1282.

43.          Gillespie SK, Zhang XD, Hersey P. Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells. Mol Cancer Ther 2004; 3: 1651-1658.

44.          Mousavi SH, Zhang X, Gillespie S, Wachter E, Hersey P. Rose Bengal induces dual modes of cell death in melanoma cells and has clinical activity against melanoma. Melanoma Res 2006; 16: S8.

45.          Ashkenazi A, Dixit VM.Death receptors: Signaling and modulation. Science 1998; 281: 1305-1308.

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

47.          Cryns V, Yuan J. Proteases to die for. Genes Dev 1998; 12: 1551-1570.

48.          Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998; 281:1312-1316.

49.          Igney FH, Krammer PH. Death and anti-death: Tumour resistance to apoptosis. Nat Rev Cancer 2002; 2: 77-88.

50.          Fischer U, Schulze-Osthoff K. New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev 2005; 57:187-215.

51.          Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell 2001; 104: 87-501.

52.          Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem 1997; 272: 32401-32410

53.          Peter ME, Krammer PH. Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis. Curr Opin Immunol 1998; 10: 45-51.

54.          Rubio-Moscardo F, Blesa D, Mestre C, Siebert R, Balasas T, Benito A, et al. Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes. Blood 2005; 106: 214-22.

55.          Suliman A, Lam A, Datta R, Srivastava RK. Intracellular mechanisms of TRAIL: Apoptosis through mitochondrial-dependent and -independent pathways. Oncogene 2001; 20: 2122-2133

56.          Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation. Cell 1995; 81:495-504.

57.          Wajant H. The Fas signaling pathway: More than a paradigm. Science 2002; 296:635-636.

58.          Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 1995; 14:  55-88.

59.          Kataoka T, Ter MHahne M, Schneider P, Irmler M, Thome M, et al. FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation. J Immunol 1998; 161:3936-3942.

60.          Scaffidi C, Schmitz I, Krammer PH, Peter ME. The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 1999; 274:1541-1548.

61.          Hitoshi Y, Lorens J, Kitada SI, Fisher J, LaBarge M, Ring HZ, et al. Toso, a cell surface, specific regulator of Fas-induced apoptosis in T cells. Immunity 1998; 8:461-471.

62.          Leblanc V, Delumeau I, Tocque B. Ras-GTPase activating protein inhibition specifically induces apoptosis of tumour cells. Oncogene 1999; 18:4884-4889.

63.          Zhang XD, Borrow JM, Zhang XY, Nguyen T, Hersey P. Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene 2003; 22:2869-2881.

64.          Gillespie S, Borrow J, Zhang XD, Hersey P. Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. Apoptosis 2006; 11:251-265.

65.          Bron LP, Scolyer RA, Thompson JF, Hersey P. Histological expression of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in human primary melanoma. Pathology 2004; 36:561-565.

66.          Zhang XD, Wu JJ, Gillespie S, Borrow J, Hersey P. Human melanoma cells selected for resistance to apoptosis by prolonged exposure to tumor necrosis factor-related apoptosis-inducing ligand are more vulnerable to necrotic cell death induced by cisplatin. Clin Cancer Res 2006; 12:1355-1364.

67.          Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, et al. Progression in melanoma is associated with decreased expression of death receptors for tumor necrosis factor-related apoptosis-inducing ligand. Hum Pathol 2006; 37:1286-1294.

68.          Hersey P, Zhang XD. Resistance of follicular lymphoma cells to chemotherapy is more than just Bcl-2. Cancer Biol Ther 2003; 2:541-543.

69.          Wu JJ, Zhang XD, Gillespie S, Hersey P. Selection for TRAIL resistance results in melanoma cells with high proliferative potential. FEBS Lett 2005; 579:1940-1944.

70.          Chen LH, Jiang CC, Kiejda KA, Wang YF, Thorne RF, Zhang XD, et al. Thapsigargin sensitizes human melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-R2 through the unfolded protein response. Carcinogenesis 2007; 28:2328-2336.

71.          Zhang XD, Gillespie SK, Borrow JM, Hersey P. The histone deacetylase inhibitor suberic bishydroxamate: A potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. Biochem Pharmacol 2003; 66:1537-1545.

72.          Zhang XY, Zhang XD, Borrow JM, Nguyen T, Hersey P. Translational Control of Tumor Necrosis Factor-related Apoptosis-inducing Ligand Death Receptor Expression in Melanoma Cells. J Biol Chem2004; 279:10606-10614.

73.          Chen CJ, Li HC, Gillespie S, Kiejda KA, Mhaidat N, Yu FW, et al. Tunicamycin sensitizes human melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by up-regulation of TRAIL-R2 via the unfolded protein response. Cancer Res2007; 67:5880-2885.

74.          Gillespie S, Zhang XD, Hersey P. Variable expression of protein kinase CE in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis. Mol cancer ther 2005; 4:668-676.

75.          Human Protein Reference Database.2008. Available at: http: www.hprd.org

76.          ExPASy Proteomics Server. 2008. Available at: http: ca.expasy.org

77.          Saelens X, Festjens N, Vande Walle L, Van Gurp M, Van Loo G, Vandenabeele P. Toxic proteins released from mitochondria in cell death. Oncogene 2004; 23:2861-2874.

78.          Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102:33-42.

79.          Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C, Kroemer G. Mechanisms of cytochrome c release from mitochondria. Cell Death Differ 2006; 13:1423-1433.

80.          Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman CW. Apoptosis is induced by β-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci USA 1993; 90:7951-7958.

81.          Chinnaiyan AM. The apoptosome: heart and soul of the cell death machine. Neoplasia (New York, NY) 1999; 1:5-15.

82.          Hill MM, Adrain C, Duriez PJ, Creagh EM, Martin SJ. Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes. EMBO J 2004; 23:134-145.

83.          Schimmer AD. Inhibitor of apoptosis proteins: Translating basic knowledge into clinical practice. Cancer Res 2004; 64:7183-7190.

84.          Van Loo G, Van Gurp M, Depuydt B, Srinivasula SM, Rodriguez I, Alnemri ES, et al. The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ 2002; 9:20-26.

85.          Ekert PG, Vaux DL. The mitochondrial death squad: Hardened killers or innocent bystanders? Curr Opin Cell Biol 2005; 17:626-630.

86.          Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersey P. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 1999; 59:2747-2753.

87.          Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CYJ, et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 2001; 410:549-554.

88.          Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M, et al. Two distinct pathways leading to nuclear apoptosis. J Ex Med 2000; 192:571-579.

89.          Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001; 412:95-99.

90.          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.

91.          Zhang XD, Gillespie SK, Hersey P. Staurosporine induces apoptosis of melanoma by both caspase-dependent and -independent apoptotic pathways. Mol cancer ther 2004; 3:187-197.

92.          Cory S, Adams JM. The Bcl-2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer 2002; 2:647-656.

93.          Schuler M, Green DR. Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 2001; 29: 684-688.

94.          Gross A, McDonnell JM, Korsmeyer SJ. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev 1999; 13:1899-1911.

95.          Esposti MD. The roles of Bid. Apoptosis 2002;7:433-440

96.          Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94:491-501.

97.          Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not Bcl-X(L). Cell 1996; 87:619-628.

98.          Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-x(L), and Bcl-2, displaces Bax and promotes cell death. Cell 1995; 80:285-291.

99.          Newmeyer DD, Bossy-Wetzel E, Kluck RM, Wolf BB, Beere HM, Green DR. Bcl-x(L) does not inhibit the function of Apaf-1. Cell Death Differ 2000; 7:402-407.

100.        Chau BN, Cheng EHY, Kerr DA, Hardwick JM. Aven, a novel inhibitor of caspase activation, binds Bcl-X(L) and Apaf-1. Mol Cell 2000; 6:31-40.

101.        Liu FT, Newland AC, Jia L. Bax conformational change is a crucial step for PUMA-mediated apoptosis in human leukemia. Biochem Biophys Res Commun 2003; 310:956-962.

102.        Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288:1053-1058.

103.        Meyer N, Kim SS, Penn LZ. The Oscar-worthy role of Myc in apoptosis. Semin Cancer Biol 2006; 16:275-287.

104.        Sharifi AM, Mousavi SH, Farhadi M, Larijani B. Study of high glucose-induced apoptosis in PC12 cells: Role of bax protein. J Pharm Sci 2007; 104:258-262.

105.        Sharifi AM, Mousavi SH. Studying the effects of lead on DNA fragmentation and proapoptotic Bax and antiapoptotic Bcl-2 protein expression in PC12 cells. Toxicol Mech Methods 2008; 18:75-79.

106.        Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Reports 2006; 7: 880-885.

107.        Faitova J, Krekac D, Hrstka R, Vojtesek B. Endoplasmic reticulum stress and apoptosis. Cell Mol Biol Lett 2006; 11: 488-505.

108.        Chen CJ, Li HC, Gillespie S, Yu FW, Kiejda KA, Xu DZ, et al. Inhibition of MEK sensitizes human melanoma cells to endoplasmic reticulum stress-induced apoptosis. Cancer Res 2007; 67: 9750-9761.

109.        Lipson KL, Fonseca SG, Urano F. Endoplasmic reticulum stress-induced apoptosis and auto-immunity in diabetes. Curr Mol Med 2006; 6: 71-7.

110.        Oakes SA, Lin SS, Bassik MC. The control of endoplasmic reticulum-initiated apoptosis by the Bcl-2 family of proteins. Curr Mol Med 2006; 6: 99-109.

111.        Takuma K, Yan SS, Stern DM, Yamada K. Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer's disease. J Pharmacol Sci 2005; 97: 312-316.

112.        Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: A control point for apoptosis. Science 2003; 300: 135-139.

113.        Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003; 22: 8608-8618.

114.        Turk V, Turk B, Turk D. Lysosomal cysteine proteases: Facts and opportunities. EMBO J 2001; 20: 4629-4633.

115.        Wyllie AH, Golstein P. More than one way to go. Proc Natl Acad Sci USA 2001; 98: 11-3.

116.        Herr I, Debatin KM. Cellular stress response and apoptosis in cancer therapy. Blood 2001; 98: 2603-2614.

117.        Boya P, Andreau K, Poncet D, Zamzami N, Perfettini JL, Metivier D, et al. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J Experiment Med 2003; 197: 1323-1334.

118.        Guicciardi ME, Deussing J, Miyoshi H, Bronk SF, Svingen PA, Peters C, et al. Cathepsin B contributes to TNF-?-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest 2000; 106: 1127-1137.

119.        Stoka V, Turk B, Schendel SL, Kim TH, Cirman T, Snipas SJ, et al. Lysosomal protease pathways to apoptosis: Cleavage of Bid, not pro-caspases, is the most likely route. J Biol Chem 2001; 276: 3149-3157.

120.        Emert-Sedlak L, Shangary S, Rabinovitz A, Miranda MB, Delach SM, Johnson DE. Involvement of cathepsin D in chemotherapy-induced cytochrome c release, caspase activation, and cell death. Mol Cancer Ther 2005; 4: 733-742.

121.        Hersey P, Zhang XD. Adaptation to ER stress as a driver of malignancy and resistance to therapy in human melanoma. Pigment Cell Melanoma Res 2008; 21: 358-367.

122.        Li HC, Chen CJ, Watts R, Thorne RF, Kiejda KA, Xu DZ, et al. Inhibition of endoplasmic reticulum stress-induced apoptosis of melanoma cells by the ARC protein. Cancer Res 2008; 68: 834-842.

123.        Ekegren T, Grandstrom E, Lindholm D, Aquilonius SM. Upregulation of Bax protein and increased DNA degradation in ALS spinal cord motor neurons. Acta Neurol Scand 1999; 100: 317-321.

124.        Mousavi SH, Mousavi SH. Lysosome: as a proposed target for rose bengal in inducing cell death in melanoma cells. Iran J Med Hypotheses and Ideas 2008; 2(12):79-92.

125.        Ionov Y, Yamamoto H, Krajewski S, Reed JC, Perucho M. Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc Nat Acad Sci USA 2000; 97: 10872-10877.

126.        Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59: 2615-2622.

127.        Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol 2001; 13: 555-562.

128.        Makin G, Hickman JA. Apoptosis and cancer chemotherapy. Cell Tissue Res 2000; 301: 143-152.

129.        Albanell J, Codony J, Rovira A, Mellado B, Gasco?n P. Mechanism of action of anti-HER2 monoclonal antibodies: Scientific update on trastuzumab and 2C4. Adv Exp Med Biol 2003; 532 253-268.

130.        Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 2001; 7: 1459-1465.

131.        Normanno N, Campiglio M, De Luca A, Somenzi G, Maiello M, Ciardiello F, et al. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol 2002; 13: 65-72.

132.        Barnes CJ, Bagheri-Yarmand R, Mandal M, Yang Z, Clayman GL, Hong WK, et al. Suppression of epidermal growth factor receptor, mitogen-activated protein kinase, and Pak1 pathways and invasiveness of human cutaneous squamous cancer cells by the tyrosine kinase inhibitor ZD1839 (Iressa). Mol Cancer Ther 2003; 2: 345-351.

133.        Fujimura M, Hidaka T, Saito S. Selective inhibition of the epidermal growth factor receptor by ZD1839 decreases the growth and invasion of ovarian clear cell adenocarcinoma cells. Clin Cancer Res 2002; 8: 2448-2454.

134.        Hirata A, Ogawa SI, Kometani T, Kuwano T, Naito S, Kuwano M, et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 2002; 6: 2554-2560.

135.        MacCorkle RA, Freeman KW, Spencer DM. Synthetic activation of caspases: artificial death switches. Proc Nat Acad Sci USA 1998; 95: 3655-3660.

136.        Yan S, Sameni M, Sloane BF. Cathepsin B and human tumor progression. Biol Chem 1998; 379: 113-123.

137.        Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ 2001;8: 569-581.

138.        Mousavi SH, Zhang XD, Sharifi AM, Hersey P. Study of rose bengal-induced cell death in melanoma cells in the absence of light. Iran J Basic Med Sci 2008; 9:216-222.

139.        Tavakkol Afshari J, Brook A, Mousavi SH. Study of cytotoxic and apoptogenic properties of saffron extract in human cancer cell lines. Food Chem Toxicol 2008; 8:3443-3447.

140.        Linder S, Shoshan MC. Lysosomes and endoplasmic reticulum: targets for improved, selective anticancer therapy. Drug Resist Updat 2005; 8: 199-204.

141.        Brunner T, Wasem C, Torgler R, Cima I, Jakob S, Corazza N. Fas (CD95/Apo-1) ligand regulation in T cell homeostasis, cell-mediated cytotoxicity and immune pathology. Semin Immunol 2003; 15:167-76.

142.        Elkon K. Autoantibodies in systemic lupus erythematosus. Curr Opin Rheumatol 1995; 7:384-388.

143.        Casciola-Rosen L, Rosen A, Petri M, Schlissel M. Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: Implications for coagulation events and antigenic spread in systemic lupus erythematosus. Proc Natl Acad Sci USA 1996; 93:1624-9.

144.        Botto M, Dell'Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Gene 1998; 19:56-59.

145.        Morgan BP, Walport MJ. Complement deficiency and disease. Immunol Today 1991; 12: 301-306.

146.        Rordorf C, Schnebli HP, Baltz ML. The acute-phase response in (NZB x NZW) F1 and MRL/l mice. Contrasting patterns resembling those in human systemic lupus erythematosus and rheumatoid arthritis, respectively. J Ex Med 1982; 156:1268-73.

147.        Taylor PR, Carugati A, Fadok VA, Cook HT, Andrews M, Carroll MC, et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 2000; 192:359-366.

148.        Mysler E, Bini P, Drappa J, Ramos P, Friedman SM, Krammer PH, et al. The apoptosis-1/Fas protein in human systemic lupus erythematosus. J Clin Invest 1994; 93:1029-1034.

149.        Ohsako S, Hara M, Harigai M, Fukasawa C, Kashiwazaki S. Expression and function of Fas antigen and Bcl-2 in human systemic lupus erythematosus lymphocytes. Clin Immunol Immunopathol 1994; 73: 109-114.

150.        Chu EB, Hobbs MV, Wilson CB, Romball CG, Linsley PS, Weigle WO. Intervention of CD4+ cell subset shifts and autoimmunity in the BXSB mouse by murine CTLA4Ig. J Immunol 1996; 156: 1262-1268.

151.        Davis JC, Totoritis MC, Rosenberg J, Sklenar TA, Wofsy D. Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J heumatol 2001; 28: 95-101.

152.        Mihara M, Tan I, Chuzhin Y, Reddy B, Budhai L, Holzer A, et al. CTLA4Ig inhibits T cell-dependent B-cell maturation in murine systemic lupus erythematosus. J Clin Invest 2000; 106:91-101.

153.        Bouillet P, Metcalf D, Huang DCS. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286: 1735-1738.

154.        Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 2000; 25: 177-181.

155.        Hayashida K, Shimaoka Y, Ochi T, Lipsky PE. Rheumatoid arthritis synovial stromal cells inhibit apoptosis and up- regulate Bcl-X(L) expression by B cells in a CD49/CD29-CD106-dependent mechanism. J Immunol 2000; 164: 1110-1116.

156.        Matsumoto S, ller-Ladner U, Gay RE, Nishioka K, Gay S. Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts. J Rheumatol 1996; 23: 1345-1352.

157.        Pap T, Franz JK, Kuchen S. Expression of Survivin, a novel anti-apoptotic molecule, in the synovium of patients with rheumatoid arthritis (RA). Arthritis Rheum 1998; 41.

158.        Sioud M, Mellbye O, Førre Ø. Analysis of the NF-κB p65 subunit, Fas antigen, Fas ligand and Bcl-2- related proteins in the synovium of RA and polyarticular JRA. Clin Exp Rheumatol 1998; 16: 125-134.

159.        Lee SC, Pervaiz S. Apoptosis in the pathophysiology of diabetes mellitus. Int J Biochem Cell Biol 2007; 39: 497-504.

160.        Heimbrook DC, Oliff A. Therapeutic intervention and signalingCurr Opin Cell Biol 1998; 10: 284-288.

161.        Itoh N, Imagawa A, Hanafusa T, Waguri M, Yamamoto K, Iwahashi H, et al. Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J Exp Med 1997; 186: 613-618.

162.        Kagi D, Odermatt B, Ohashi PS, Zinkernagel RM, Hengartner H. Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity. J Exp Med 1996; 183: 2143-2152.

163.        Yang XD, Tisch R, Singer SM, Cao ZA, Liblau RS, Schreiber RD, et al. Effect of tumor necrosis factor α on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J Exp Med 1994; 180: 995-1004.

164.        Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 2004; 199: 1467-1477.

165.        Yang Z, Chen M, Ellett JD, Fialkow LB, Carter JD, McDuffie M, et al. Autoimmune diabetes is blocked in Stat4-deficient mice. J Autoimmun 2004; 22: 191-200.

166.        Dowling P, Shang G, Raval S, Menonna J, Cook S, Husar W. Involvement of the CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis brain. J Exp Med 1996; 184: 1513-1518.

167.        Hisahara S, Okano H, Miura M. Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination. Neurosci Res 2003; 46: 387-397.

168.        Sharief MK, Semra YK, Seidi OA, Zoukos Y. Interferon-b therapy downregulates the anti-apoptosis protein FLIP in T cells from patients with multiple sclerosis. J Neuroimmunol 2001; 120: 199-207.

169.        Kuhlmann T, Lucchinetti C, Zettl UK, Bitsch A, Lassmann H, ck W. Bcl-2-expressing oligodendrocytes in multiple sclerosis lesions. GLIA 1999; 28: 34-39.

170.        Sharief MK, Matthews H, Noori MA. Expression ratios of the Bcl-2 family proteins and disease activity in multiple sclerosis. J Neuroimmunol 2003; 134: 158-165.

171.        Hebb ALO, Moore CS, Bhan V, Robertson GS. Targeting apoptosis to treat multiple sclerosis. Curr Drug Discov Technol 2008; 5:75-7.

172.        Jenner P, Olanow CW. Understanding cell death in Parkinson's disease. Ann Neurol 1998; 44: (SUPPL. 1): S72-84

173.        Mochizuki H, Hayakawa H, Migita M, Shibata M, Tanaka R, Suzuki A, et al. An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease. Proc Nat Acad Sci USA 2001; 98: 10918-10923.

174.        Anglade P. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol Histopathol 1997; 12: 25-31.

175.        Tatton NA, Kish SJ. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience 1997; 77: 1037-1048.

176.        Tatton NA, Lean-Fraser A, Tatton WG, Perl DP, Olanow CW. A fluorescent double labelling method to detect and confirm apoptotic nuclei in Parkinson's disease. Ann Neurol 1998; 44: S142-8. Review.

177.        Hassouna I, Wickert H, Zimmermann M, Gillardon F. Increase in bax expression in substantia nigra following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment of mice. Neurosci Lett 1996; 204: 85-88.

178.        Tatton WG, Chalmers-Redman R, Brown D, Tatton N, Schapira, Hunot, et al. Apoptosis in Parkinson's disease: signals for neuronal degradation. Ann Neurol 2003; 53: (SUPPL. 3): S61-70

179.        Cummings JL, Vinters HV, Cole GM, Khachaturian ZS. Alzheimer's disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology 1998;51(1 SUPPL.): 2-17.

180.        Su JH, Anderson AJ, Cummings BJ, Cotman CW. Immunohistochemical evidence for apoptosis in Alzheimer's disease. NeuroReport 1994; 5: 2529-2533.

181.        Forloni G, Bugiani O, Tagliavini F, Salmona M. Apoptosis-mediated neurotoxicity induced by β-amyloid and PRP fragments. Mol Chem Neuropathol 1996; 28: 163-171.

182.        Gschwind M, Huber G. Apoptotic cell death induced by β-amyloid1-42 peptide is cell type dependent. J Neurochem 1995; 65: 292-300.

183.        Martin LJ, Price AC, Kaiser A, Shaikh AY, Liu Z. Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review). Int J mol med 2000; 5: 3-13.

184.        Masliah E, Mallory M, Alford M, Tanaka S, Hansen LA. Caspase dependent DNA fragmentation might be associated with excitotoxicity in Alzheimer disease. J Neuropathol Exp Neurol 1998; 57: 1041-1052.

185.        Mattson MP, Partin J, Begley JG. Amyloid P-peptide induces apoptosis-related events in synapses and dendrites. Brain Res 1998; 807: 167-176.

186.        Mattson MP, Guo Q, Furukawa K, Pedersen WA.. Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer's disease. J Neurochem 1998; 70: 1-14.

187.        Weidemann A, Paliga K, rrwang U, Reinhard FBM, Schuckert O, Evin G, et al. Proteolytic processing of the Alzheimer's disease amyloid precursor protein within its cytoplasmic domain by caspase-like proteases. J Biol Chem 1999; 274: 5823-5829.

188.        Su JH, Deng G, Cotman CW. Bax Protein Expression Is Increased in Alzheimer's Brain: Correlations with DNA Damage, Bcl-2 Expression, and Brain Pathology. J Neuropathol Exp Neurol 1997; 56:86-93.

189.        Cotman CW. Apoptosis decision cascades and neuronal degeneration in Alzheimer's disease. Neurobiol Aging 1998; 19 (Suppl. 1):29-32

190.        Kruman I, Bruce-Keller AJ, Bredesen D, Waeg G, Mattson MP. Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J Neurosci 1997; 17:5089-50100.

191.        Mattson MP, Lindvall O. Neurotrophic factor and cytokine signaling in the aging brain. Aging Brain 1997; 2:299-345.

192.        Gibson GE, Park LCH, Zhang H, Sorbi S, Calingasan NY. Oxidative stress and a key metabolic enzyme in Alzheimer brains, cultured cells, and an animal model of chronic oxidative deficits. Ann NY Acad Sci 1999; 893:79-94.

193.        Chan SL, Griffin WST, Mattson MP. Evidence for caspase-mediated cleavage of AMPA receptor subunits in neuronal apoptosis and Alzheimer's disease. J Neurosci Res 1999; 57: 315-323.

194.        Tortosa A, pez E, Ferrer I. Bcl-2 and Bax protein expression in Alzheimer's disease. Acta Neuropathol 1998; 95: 407-412.

195.        Sawa A, Wiegand GW, Cooper J, Margolis RL, Sharp AH, Lawler J, et al. Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat Med 1999; 1194-1198.

196.        Zaidman BZ, Yassin M, Mahajna J, Wasser SP. Medicinal mushroom modulators of molecular targets as cancer therapeutics. Appl Microbiol Biotechnol 2005; 67: 453-468.