In multicellular organisms, the total number of cells is a balance between the cell-generating effects of mitosis and cell death that is induced through apoptosis. A disruption of this delicate balance can lead to the development of cancer. This Timeline article focuses on how the field of apoptosis biology has developed in the context of its contribution to our understanding of cell death, or lack of it, in the development of malignant disease. It traces the course of research from key discoveries in fundamental biology to potential therapeutic applications.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 4, 239–257 (1972).
Vogt, C. Untersuchungen über die Entwicklungsgeschichte der Geburtshelferkröte. (Alytes obstetricians) 130 (Jent und Gassman, 1842).
Glucksmann, A. Cell death in normal vertebrate ontogeny. Biol. Rev. 26, 59–86 (1951).
Saunders, J. W. Jr. Death in embryonic systems. Science 154, 604–612 (1966).
Lockshin, R. A. & Williams, C. M. Programmed cell death – 1. Cytology of degeneration in the intersegmental muscles of the pernyi silkmoth. J. Insect Physiol. 11, 123–133 (1965).
Kerr, J. F. A histochemical study of hypertrophy and ishaemic injury or rat liver with special reference to changes in lysosomes. J. Pathol. Bacteriol. 90, 419–435 (1965).
Wyllie, A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284, 555–560 (1980).
Wyllie, A. H., Kerr, J. F. & Currie, A. R. Cell death: the significance of apoptosis. Int. Rev. Cytol. 68, 251–306 (1980).
Enari, M. et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43–50 (1998).
Horvitz, H. R. Nobel lecture. Worms, life and death. Biosci. Rep. 5, 239–303 (2003).
Kerr, J. F., Winterford, C. M. & Harmon, B. V. Apoptosis. Its significance in cancer and cancer therapy. Cancer 73, 2013–2026 (1994).
Lowe, S. W. et al. P53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74, 957–967 (1993).
McGahon, A. et al. BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death. Blood 83, 1179–1187 (1994).
Krammer, P. H. et al. CD95(APO-1/Fas)-mediated apoptosis in normal and malignant liver, colon, and hematopoietic cells. Adv. Cancer Res. 75, 251–273 (1998).
Tsujimoto, Y. et al. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226, 1097–1099 (1984).
Tsujimoto, Y. & Croce, C. M. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl Acad. Sci. USA 83, 5214–5218 (1986).
Cleary, M. L., Smith, S. D. & Sklar, J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47, 19–28 (1986).
Vaux, D. L. Early work on the function of Bcl-2, an interview with David Vaux. Cell Death Differ. 11, S28–S32 (2004).
Rowley, J. D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and giemsa staining. Nature 243, 290–293 (1973).
Vaux, D. L, Cory, S. & Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442 (1988).
Tsujimoto, Y. Stress-resistance conferred by high level of bcl-2 alpha protein in human B lymphoblastoid cell. Oncogene 11, 1331–1336 (1989).
Williams, G. T. et al. Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis. Nature 343, 76–79 (1990).
Rodriguez-Tarduchy, G., Collins, M. & López-Rivas, A. Regulation of apoptosis in interleukin-3-dependent hemopoietic cells by interleukin-3 and calcium ionophores. EMBO J. 9, 2997–3002 (1990).
Crompton, T. IL3-dependent cells die by apoptosis on removal of their growth factor. Growth Factors 4, 109–116 (1991).
Reed, J. C. et al. Oncogenic potential of bcl-2 demonstrated by gene transfer. Nature 336, 259–261 (1988).
McDonnell, T. J. et al. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57, 79–88 (1989).
Reed, J. C. et al. Antisense-mediated inhibition of BCL2 protooncogene expression and leukemic cell growth and survival: comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides. Cancer Res. 50, 6565–6570 (1990).
Hockenbery, D. et al. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348, 334–336 (1990).
Liu, X. et al. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86, 147–157 (1996).
Yang, J. et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275, 1129–1132 (1997).
Creagh, E. M., Conroy, H. & Martin, S. J. Caspase-activation pathways in apoptosis and immunity. Immunol. Rev. 193, 10–21 (2003).
Kroemer, G., Galluzzi, L. & Brenner, C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99–163 (2007).
Boise, L. H. et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597–608 (1993).
Gibson, L. et al. bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene 13, 665–675 (1996 ).
Kozopas, K. M. et al. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc. Natl Acad. Sci. USA 90, 3516–3520 (1993).
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 102, 33–42 (2000).
Verhagen, A. M. et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43–53 (2000).
Oltvai, Z. N., Milliman, C. L. & Korsmeyer, S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74, 609–619 (1993).
Chittenden, T. et al. Induction of apoptosis by the Bcl-2 homologue Bak. Nature 374, 733–736 (1995).
O'Connor, L. et al. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 17, 384–395 (1998).
Wang, K. et al. BID: a novel BH3 domain-only death agonist. Genes Dev. 10, 2859–2869 (1996).
Yang, E. et al. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80, 285–291 (1995).
Yip, K. W. & Reed, J. C. Bcl-2 family proteins and cancer. Oncogene 27, 6398–6406 (2008).
Monni, O. et al. BCL2 over-expression associated with chromosomal amplification in diffuse large B-cell lymphoma. Blood 90, 1168–1174 (1997).
Ikegaki, N. et al. Expression of bcl-2 in small cell lung carcinoma cells. Cancer Res. 54, 6–8 (1994).
Hanada, M. et al. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 82, 1820–1828 (1993).
Cimmino, A. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl Acad. Sci. USA 102, 13944–13949 (2005).
Miyashita, T. et al. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 6, 1799–1805 (1994).
Miyashita, T. & Reed, J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293–299 (1995).
Oda, E. et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288, 1053–1058 (2000).
Sax, J. K. et al. BID regulation by p53 contributes to chemosensitivity. Nature Cell Biol. 11, 842–849 (2002).
Yu, J., Zhang, L., Hwang, P. M., Kinzler, K. W. & Vogelstein, B. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol. Cell 7, 673–682 (2001).
Nakano, K. & Vousden, K. H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7, 683–694 (2001).
Ranger, A. M. et al. Bad-deficient mice develop diffuse large B cell lymphoma. Proc. Natl Acad. Sci. USA 100, 9324–9329 (2003).
Zinkel, S. S. et al. A role for proapoptotic BID in the DNA-damage response. Cell 122, 579–591 (2005).
Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999).
Gascoyne, R. D. et al. Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma. Blood 90, 244–251 (1997).
Gobe, G. E. et al. Apoptosis and expression of Bcl-2, Bcl-XL, and Bax in renal cell carcinomas. Cancer Invest. 20, 324–332 (2002).
Ayhan, A. et al. Loss of heterozygosity at the bcl-2 gene locus and expression of bcl-2 in human gastric and colorectal carcinomas. Jpn J. Cancer Res. 85, 584–591 (1994).
Castle, V. P. et al. Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification. Am. J. Pathol. 143, 1543–1550 (1993).
Casado, S. et al. Predictive value of P53, BCL-2, and BAX in advanced head and neck carcinoma. Am. J. Clin. Oncol. 25, 588–590 (2002).
Gradilone, A. et al. Survivin, bcl-2, bax, and bcl-X gene expression in sentinel lymph nodes from melanoma patients. J. Clin. Oncol. 21, 306–312 (2003). .
Stavropoulos, N. E. et al. Prognostic significance of p53, bcl-2 and Ki-67 in high risk superficial bladder cancer. Anticancer Res. 22, 3759–3764 (2002).
Chang, J. et al. Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor. Cancer 97, 545–553 (2003).
Bargou, R. C. et al. Expression of the bcl-2 gene family in normal and malignant breast tissue: low bax-alpha expression in tumor cells correlates with resistance towards apoptosis. Int. J. Cancer. 60, 854–859 (1995).
Krajewski, S. et al. Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. Cancer Res. 55, 4471–4478 (1995).
Sjöström, J. et al. A multivariate analysis of tumour biological factors predicting response to cytotoxic treatment in advanced breast cancer. Br. J. Cancer 78, 812–815 (1998).
Krajewski, S. et al. Prognostic significance of apoptosis regulators in breast cancer. Endocr. Relat. Cancer 6, 29–40 (1999).
Kymionis, G. D. et al. Can expression of apoptosis genes, bcl-2 and bax, predict survival and responsiveness to chemotherapy in node-negative breast cancer patients? J. Surg. Res. 99, 161–168 (2001).
Letai, A. G. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nature Rev. Cancer 8, 121–132 (2008).
Sentman, C. L. et al. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67, 879–888 (1991).
Webb, A. et al. BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 349, 1137–1141 (1997).
Lessene, G., Czabotar, P. E. & Colman, P. M. BCL-2 family antagonists for cancer therapy. Nature Rev. Drug Discov. 7, 989–1000 (2008).
Askew, D. S., Ashmun, R. A., Simmons, B. C. & Cleveland, J. L. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene 19, 15–22 (1991).
Shi, Y. et al. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science 257, 212–214 (1992).
Evan, G. I. et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 69, 119–128 (1992).
Strasser, A., Harris, A. W, Bath, M. L. & Cory, S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348, 331–333 (1990).
Soucie, E. L. et al. Myc potentiates apoptosis by stimulating Bax activity at the mitochondria. Mol. Cell. Biol. 21, 4725–4736 (2001).
de Alborán, I. M. Baena, E. & Martinez- A. C. c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death. Cell Death Differ. 11, 61–68 (2004).
Eischen, C. M. et al. Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1. Oncogene 20, 6983–6993 (2001).
Maclean, K. H. et al. c-Myc augments gamma irradiation-induced apoptosis by suppressing Bcl-XL. Mol. Cell. Biol. 23, 7256–7270 (2003).
Dansen, T. B. et al. Specific requirement for Bax, not Bak, in Myc-induced apoptosis and tumor suppression in vivo. J. Biol. Chem. 281, 10890–10895 (2006).
Felsher, D. W. & Bishop, J. M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).
Pelengaris, S. et al. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol. Cell 3, 565–577 (1999).
Yonish-Rouach, E. et al. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352, 345–347 (1991).
Zhan, Q. et al. Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. Oncogene 9, 3743–3751 (1994).
Lapenko, O. & Prives, C. Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ. 13, 951–961 (2006).
Trauth, B. C. et al. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245, 301–305 (1989).
Yonehara, S., Ishii, A. & Yonehara, M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J. Exp. Med. 169, 1747–1756 (1989).
Itoh, N. et al. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66, 233–243 (1991).
Suda, T., Takahashi, T., Golstein, P. & Nagata, S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75, 1169–1178 (1993).
Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 (1993).
Johnstone, R. W., Frew, A. J. & Smyth, M. J. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nature Rev. Cancer 8, 782–798 (2008).
Pitti, R. M. et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J. Biol. Chem. 271, 12687–12690 (1996).
Wiley, S. R. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995).
Friesen, C., Herr, I., Krammer, P. H. & Debatin, K. M. Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nature Med. 2, 574–577 (1996).
Fulda, S., Susin, S. A., Kroemer, G. & Debatin, K. M. Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res. 58, 4453–4460 (1998).
Müller, M. et al. Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J. Clin. Invest. 99, 403–413 (1997). .
Müller, M. et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med. 188, 2033–2045 (1998).
Bellgrau, D. et al. A role for CD95 ligand in preventing graft rejection. Nature 377, 630–632 (1995).
Griffith, T. S. et al. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270, 1189–1192 (1995).
Strand, S. et al. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells — a mechanism of immune evasion? Nature Med. 2, 1361–1366 (1996).
Hahne, M. et al. Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape. Science 274, 1363–1366 (1996).
Allison, J., Georgiou, H. M., Strasser, A. & Vaux, D. L. Transgenic expression of CD95 ligand on islet β cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts. Proc. Natl Acad. Sci. USA 94, 3943–3947 (1997).
Oltersdorf, T. et al. An inhibitor of the Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005).
Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).
Being asked to write this Timeline article is a privilege and in no way reflects my contribution to the field compared with the many giants who have made groundbreaking advances over the past several decades. Trying to get the balance right between the fundamental biology of apoptosis and how it has contributed to our understanding of cancer has not been easy in a limited space. I regret not being able to cite all the major contributions to this field, and to those colleagues whose work I should have cited, but inadvertently did not, I humbly apologize.
The author declares no competing financial interests.
About this article
A potential role of calpains in sulfonylureas (SUs) –mediated death of human pancreatic cancer cells (1.2B4)
Toxicology in Vitro (2021)
Novel urea linked ciprofloxacin-chalcone hybrids having antiproliferative topoisomerases I/II inhibitory activities and caspases-mediated apoptosis
Bioorganic Chemistry (2021)
LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK–eIF2α–ATF4–CHOP axis
Acta Pharmacologica Sinica (2021)
Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling
Lung Cancer: Targets and Therapy (2021)
Boswellia sacra essential oil manages colon cancer stem cells proliferation and apoptosis: a new perspective for cure
Journal of Essential Oil Research (2021)