Abstract
Deregulation of Bcl2 family members is a frequent feature of human malignant diseases and causal for therapy resistance. A number of studies have recently shed light onto the role of pro- and anti-apoptotic Bcl2 family members in tumour-pathogenesis and in mediating the effects of classical as well as novel front-line anticancer agents, allowing the development of more efficient and more precisely targeted treatment regimens. Most excitingly, recent progress in our understanding of how Bcl2-like proteins maintain or perturb mitochondrial integrity has finally enabled the development of rational-design based anticancer therapies that directly target Bcl2 regulated events at the level of mitochondria. This review aims to give an overview on the most recent findings on the role of the Bcl2 family in tumour development in model systems of cancer, to relate these findings with observations made in human pathologies and drug-action.
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References
Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59. doi:10.1038/nrm2308
Huang DC, Adams JM, Cory S (1998) The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4. EMBO J 17:1029–1039. doi:10.1093/emboj/17.4.1029
Willis SN, Adams JM (2005) Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 17:617–625. doi:10.1016/j.ceb.2005.10.001
Chen L, Willis SN, Wei A et al (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403. doi:10.1016/j.molcel.2004.12.030
Certo M, Moore Vdel G, Nishino M et al (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351–365. doi:10.1016/j.ccr.2006.03.027
Letai A, Bassik M, Walensky L, Sorcinelli M, Weiler S, Korsmeyer S (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2:183. doi:10.1016/S1535-6108(02)00127-7
Kuwana T, Bouchier-Hayes L, Chipuk JE et al (2005) BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17:525–535. doi:10.1016/j.molcel.2005.02.003
Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42. doi:10.1016/j.cell.2007.12.018
Bakhshi A, Jensen JP, Goldman P et al (1985) Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41:899–906. doi:10.1016/S0092-8674(85)80070-2
Tsujimoto Y, Yunis J, Onorato-Showe L, Erikson J, Nowell PC, Croce CM (1984) Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science (NY) 224:1403–1406
McDonnell TJ, Korsmeyer SJ (1991) Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 349:254–256. doi:10.1038/349254a0
Egle A, Harris AW, Bath ML, O’Reilly L, Cory S (2004) VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103:2276–2283. doi:10.1182/blood-2003-07-2469
Kumar A, Ta D, Henderson D et al (1999) bcl2 and v-abl oncogenes cooperate to immortalize murine B cells that secrete antigen specific antibodies. Immunol Lett 65:153–159. doi:10.1016/S0165-2478(98)00085-6
Acton D, Domen J, Jacobs H, Vlaar M, Korsmeyer S, Berns A (1992) Collaboration of PIM-1 and BCL-2 in lymphomagenesis. Curr Top Microbiol Immunol 182:293–298
Strasser A, Harris AW, Bath ML, Cory S (1990) Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348:331–333. doi:10.1038/348331a0
Swanson PJ, Kuslak SL, Fang W et al (2004) Fatal acute lymphoblastic leukemia in mice transgenic for B cell-restricted bcl-xL and c-myc. J Immunol 172:6684–6691
Naik P, Karrim J, Hanahan D (1996) The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. Genes Dev 10:2105–2116. doi:10.1101/gad.10.17.2105
Pelengaris S, Khan M, Evan GI (2002) Suppression of Myc-induced apoptosis in β cells exposes multiple oncogenic properties of myc and triggers carcinogenic progression. Cell 109:321–334. doi:10.1016/S0092-8674(02)00738-9
Pena JC, Rudin CM, Thompson CBA (1998) Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas. Cancer Res 58:2111–2116
Zhou P, Levy NB, Xie H et al (2001) MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Blood 97:3902–3909. doi:10.1182/blood.V97.12.3902
Nieborowska-Skorska M, Hoser G, Kossev P, Wasik MA, Skorski T (2002) Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis. Blood 99:4531–4539. doi:10.1182/blood.V99.12.4531
D’Sa-Eipper C, Subramanian T, Chinnadurai G (1996) bfl-1, a bcl-2 homologue, suppresses p53-induced apoptosis and exhibits potent cooperative transforming activity. Cancer Res 56:3879–3882
Chuang PI, Morefield S, Liu CY, Chen S, Harlan JM, Willerford DM (2002) Perturbation of B-cell development in mice overexpressing the Bcl-2 homolog A1. Blood 99:3350–3359. doi:10.1182/blood.V99.9.3350
Binder C, Marx D, Overhoff R, Binder L, Schauer A, Hiddemann W (1995) Bcl-2 protein expression in breast cancer in relation to established prognostic factors and other clinicopathological variables. Ann Oncol 6:1005–1010
Joensuu H, Pylkkanen L, Toikkanen S (1994) Bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 145:1191–1198
Lee KH, Im SA, Oh DY et al (2007) Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy. BMC Cancer 7:63. doi:10.1186/1471-2407-7-63
Inada T, Kikuyama S, Ichikawa A, Igarashi S, Ogata Y (1998) Bcl-2 expression as a prognostic factor of survival of gastric carcinoma. Anticancer Res 18:2003–2010
Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW (2002) Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 1:289–298. doi:10.1016/S1535-6108(02)00047-8
Gurova KV, Gudkov AV (2003) Paradoxical role of apoptosis in tumor progression. J Cell Biochem 88:128–137. doi:10.1002/jcb.10382
Vail ME, Pierce RH, Fausto N (2001) Bcl-2 delays and alters hepatic carcinogenesis induced by transforming growth factor alpha. Cancer Res 61:594–601
de La Coste A, Mignon A, Fabre M et al (1999) Paradoxical inhibition of c-myc-induced carcinogenesis by Bcl-2 in transgenic mice. Cancer Res 59:5017–5022
Lindsten T, Ross AJ, King A et al (2000) The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol Cell 6:1389–1399. doi:10.1016/S1097-2765(00)00136-2
Zhai D, Jin C, Huang Z, Satterthwait AC, Reed JC (2008) Differential regulation of Bax and Bak by anti-apoptotic Bcl-2 family proteins Bcl-B and Mcl-1. J Biol Chem 283:9580–9586. doi:10.1074/jbc.M708426200
Dansen TB, Whitfield J, Rostker F, Brown-Swigart L, Evan GI (2006) Specific requirement for Bax, not Bak, in Myc-induced apoptosis and tumor suppression in vivo. J Biol Chem 281:10890–10895. doi:10.1074/jbc.M513655200
Juin P, Hunt A, Littlewood T et al (2002) c-Myc functionally cooperates with Bax to induce apoptosis. Mol Cell Biol 22:6158–6169. doi:10.1128/MCB.22.17.6158-6169.2002
Gillissen B, Essmann F, Hemmati PG et al (2007) Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis. J Cell Biol 179:701–715. doi:10.1083/jcb.200703040
Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L (2003) PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci USA 100:1931–1936. doi:10.1073/pnas.2627984100
Knudson CM, Johnson GM, Lin Y, Korsmeyer SJ (2001) Bax accelerates tumorigenesis in p53-deficient mice. Cancer Res 61:659–665
Yin CY, Knudson CM, Korsmeyer SJ, Van Dyke T (1997) Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 385:637–640. doi:10.1038/385637a0
Shibata MA, Liu ML, Knudson MC et al (1999) Haploid loss of bax leads to accelerated mammary tumor development in C3(1)/SV40-TAg transgenic mice: reduction in protective apoptotic response at the preneoplastic stage. EMBO J 18:2692–2701. doi:10.1093/emboj/18.10.2692
Eischen CM, Roussel MF, Korsmeyer SJ, Cleveland JL (2001) Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol Cell Biol 21:7653–7662. doi:10.1128/MCB.21.22.7653-7662.2001
Eischen CM, Rehg JE, Korsmeyer SJ, Cleveland JL (2002) Loss of Bax alters tumor spectrum and tumor numbers in ARF-deficient mice. Cancer Res 62:2184–2191
Yamamoto H, Sawai H, Perucho M (1997) Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype. Cancer Res 57:4420–4426
Rampino N, Yamamoto H, Ionov Y et al (1997) Somatic frameshift mutations in the bax gene in colon cancers of the microsatellite mutator phenotype. Science (NY) 275:967–969
Ionov Y, Yamamoto H, Krajewski S, Reed JC, Perucho M (2000) Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc Natl Acad Sci USA 97:10872–10877. doi:10.1073/pnas.190210897
Labi V, Erlacher M, Kiessling S, Villunger A (2006) BH3-only proteins in cell death initiation, malignant disease and anticancer therapy. Cell Death Differ 13:1325–1338. doi:10.1038/sj.cdd.4401940
Bouillet P, Metcalf D, Huang DCS et al (1999) Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science (NY) 286:1735–1738
Erlacher M, Labi V, Manzl C et al (2006) Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J Exp Med 203:2939–2951. doi:10.1084/jem.20061552
Egle A, Harris AW, Bouillet P, Cory S (2004) Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci USA 101:6164–6169. doi:10.1073/pnas.0401471101
Hemann MT, Bric A, Teruya-Feldstein J et al (2005) Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 436:807–811. doi:10.1038/nature03845
Ley R, Ewings KE, Hadfield K, Cook SJ (2005) Regulatory phosphorylation of Bim: sorting out the ERK from the JNK. Cell Death Differ 12:1008–1014. doi:10.1038/sj.cdd.4401688
Cragg, Kuroda J, Puthalakath H, Huang DC, Strasser A (2007) Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 4:1681–1689. doi:10.1371/journal.pmed.0040316 discussion 1690
Kuroda J, Puthalakath H, Cragg MS et al (2006) Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci USA 103:14907–14912. doi:10.1073/pnas.0606176103
Tan TT, Degenhardt K, Nelson DA et al (2005) Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7:227–238. doi:10.1016/j.ccr.2005.02.008
Hubner A, Barrett T, Flavell RA, Davis RJ (2008) Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol Cell 30:415–425. doi:10.1016/j.molcel.2008.03.025
Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA et al (2007) Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 109:271–280. doi:10.1182/blood-2006-06-026500
Tagawa H, Karnan S, Suzuki R et al (2005) Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 24:1348–1358. doi:10.1038/sj.onc.1208300
Dai DL, Wang Y, Liu M, Martinka M, Li G (2008) Bim expression is reduced in human cutaneous melanomas. J Invest Dermatol 128:403–407. doi:10.1038/sj.jid.5700989
Karst AM, Dai DL, Martinka M, Li G (2005) PUMA expression is significantly reduced in human cutaneous melanomas. Oncogene 24:1111–1116. doi:10.1038/sj.onc.1208374
Zantl N, Weirich G, Zall H et al (2007) Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance. Oncogene 26:7038–7048. doi:10.1038/sj.onc.1210510
Sinicrope FA, Rego RL, Okumura K et al (2008) Prognostic impact of bim, puma, and noxa expression in human colon carcinomas. Clin Cancer Res 14:5810–5818. doi:10.1158/1078-0432.CCR-07-5202
Labi V, Erlacher M, Kiessling S et al (2008) Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates gamma irradiation-induced thymic lymphoma development. J Exp Med 205:641–655. doi:10.1084/jem.20071658
Wick W, Petersen I, Schmutzler RK et al (1996) Evidence for a novel tumor suppressor gene on chromosome 15 associated with progression to a metastatic stage in breast cancer. Oncogene 12:973–978
Schmutte C, Tombline G, Rhiem K et al (1999) Characterization of the human Rad51 genomic locus and examination of tumors with 15q14–15 loss of heterozygosity (LOH). Cancer Res 59:4564–4569
Schmelzle T, Mailleux AA, Overholtzer M et al (2007) Functional role and oncogene-regulated expression of the BH3-only factor Bmf in mammary epithelial anoikis and morphogenesis. Proc Natl Acad Sci USA 104:3787–3792. doi:10.1073/pnas.0700115104
Jeffers JR, Parganas E, Lee Y et al (2003) Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4:321–328. doi:10.1016/S1535-6108(03)00244-7
Villunger A, Michalak EM, Coultas L et al (2003) p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science (NY) 302:1036–1038
Hemann MT, Zilfou JT, Zhao Z, Burgess DJ, Hannon GJ, Lowe SW (2004) Suppression of tumorigenesis by the p53 target PUMA. Proc Natl Acad Sci USA 101:9333–9338. doi:10.1073/pnas.0403286101
Garrison SP, Jeffers JR, Yang C et al (2008) Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Mol Cell Biol 28:5391–5402. doi:10.1128/MCB.00907-07
Yong WH, Ueki K, Chou D et al (1995) Cloning of a highly conserved human protein serine-threonine phosphatase gene from the glioma candidate region on chromosome 19q13.3. Genomics 29:533–536. doi:10.1006/geno.1995.9972
Mora J, Cheung NK, Chen L, Qin J, Gerald W (2001) Loss of heterozygosity at 19q13.3 is associated with locally aggressive neuroblastoma. Clin Cancer Res 7:1358–1361
Shimazaki C, Inaba T, Nakagawa M (2000) B-cell lymphoma-associated hemophagocytic syndrome. Leuk Lymphoma 38:121–130
Hoque MO, Begum S, Sommer M et al (2003) PUMA in head and neck cancer. Cancer Lett 199:75–81. doi:10.1016/S0304-3835(03)00344-6
Oda E, Ohki R, Murasawa H et al (2000) Noxa, a BH3-only member of the bcl-2 family and candidate mediator of p53-induced apoptosis. Science (NY) 288:1053–1058
Shibue T, Takeda K, Oda E et al (2003) Integral role of Noxa in p53-mediated apoptotic response. Genes Dev 17:2233–2238. doi:10.1101/gad.1103603
Michalak EM, Villunger A, Adams JM, Strasser A (2008) In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ 15:1019–1029
Lee SH, Soung YH, Lee JW et al (2003) Mutational analysis of Noxa gene in human cancers. APMIS 111:599–604. doi:10.1034/j.1600-0463.2003.1110602.x
Diallo JS, Aldejmah A, Mouhim AF et al (2007) NOXA and PUMA expression add to clinical markers in predicting biochemical recurrence of prostate cancer patients in a survival tree model. Clin Cancer Res 13:7044–7052. doi:10.1158/1078-0432.CCR-07-1224
Zinkel SS, Ong CC, Ferguson DO et al (2003) Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Genes Dev 17:229–239. doi:10.1101/gad.1045603
Lee JH, Soung YH, Lee JW et al (2004) Inactivating mutation of the pro-apoptotic gene BID in gastric cancer. J Pathol 202:439–445. doi:10.1002/path.1532
Krajewska M, Zapata JM, Meinhold-Heerlein I et al (2002) Expression of Bcl-2 family member Bid in normal and malignant tissues. Neoplasia 4:129–140. doi:10.1038/sj.neo.7900222
Green MM, Hutchison GJ, Valentine HR et al (2005) Expression of the proapoptotic protein Bid is an adverse prognostic factor for radiotherapy outcome in carcinoma of the cervix. Br J Cancer 92:449–458
Hayakawa J, Ohmichi M, Kurachi H et al (2000) Inhibition of BAD phosphorylation either at serine 112 via extracellular signal-regulated protein kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer cells to cisplatin. Cancer Res 60:5988–5994
Wendel HG, De Stanchina E, Fridman JS et al (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428:332–337. doi:10.1038/nature02369
Ranger AM, Zha J, Harada H et al (2003) Bad-deficient mice develop diffuse large B cell lymphoma. Proc Natl Acad Sci USA 100:9324–9329. doi:10.1073/pnas.1533446100
Lee JW, Soung YH, Kim SY et al (2004) Inactivating mutations of proapoptotic Bad gene in human colon cancers. Carcinogenesis 25:1371–1376. doi:10.1093/carcin/bgh145
Teo K, Gemmell L, Mukherjee R, Traynor P, Edwards J (2007) Bad expression influences time to androgen escape in prostate cancer. BJU Int 100:691–696. doi:10.1111/j.1464-410X.2007.07001.x
Cannings E, Kirkegaard T, Tovey SM, Dunne B, Cooke TG, Bartlett JM (2007) Bad expression predicts outcome in patients treated with tamoxifen. Breast Cancer Res Treat 102:173–179. doi:10.1007/s10549-006-9323-8
Sturm I, Stephan C, Gillissen B, Siebert R, Janz M, Radetzki S, Jung K, Loening S, Dörken B, Daniel PT (2006) Loss of the tissue-specific proapoptoptic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma. Cell Death Differ 13:619–627
Arena V, Martini M, Luongo M, Capelli A, Larocca LM (2003) Mutations of the BIK gene in human peripheral B-cell lymphomas. Genes Chromosomes Cancer 38:91–96. doi:10.1002/gcc.10245
Nakamura M, Ishida E, Shimada K, Nakase H, Sakaki T, Konishi N (2006) Defective expression of HRK is associated with promoter methylation in primary central nervous system lymphomas. Oncology 70:212–221. doi:10.1159/000094322
Higuchi T, Nakamura M, Shimada K, Ishida E, Hirao K, Konishi N (2008) HRK inactivation associated with promoter methylation and LOH in prostate cancer. Prostate 68:105–113. doi:10.1002/pros.20600
Nakamura M, Ishida E, Shimada K, Nakase H, Sakaki T, Konishi N (2005) Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas. Acta Neuropathol (Berl) 110:402–410
Obata T, Toyota M, Satoh A et al (2003) Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer. Clin Cancer Res 9:6410–6418
Kuroda J, Kimura S, Strasser A et al (2007) Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. Cell Death Differ 14:1667–1677. doi:10.1038/sj.cdd.4402168
Costa DB, Halmos B, Kumar A et al (2007) BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med 4:1669–1679. doi:10.1371/journal.pmed.0040315 discussion 1680
Gong Y, Somwar R, Politi K et al (2007) Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med 4:e294. doi:10.1371/journal.pmed.0040294
She QB, Solit DB, Ye Q, O’Reilly KE, Lobo J, Rosen N (2005) The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 8:287–297. doi:10.1016/j.ccr.2005.09.006
Inoue S, Riley J, Gant TW, Dyer MJ, Cohen GM (2007) Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa. Leukemia 21:1773–1782. doi:10.1038/sj.leu.2404760
Ploner C, Rainer J, Niederegger H et al (2007) The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. Leukemia 22:370–377
Morales AA, Gutman D, Lee KP, Boise LH (2008) BH3-only proteins Noxa, Bmf, and Bim are necessary for arsenic trioxide-induced cell death in myeloma. Blood 111:5152–5162. doi:10.1182/blood-2007-10-116889
Ramjaun AR, Tomlinson S, Eddaoudi A, Downward J (2007) Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis. Oncogene 26:970–981. doi:10.1038/sj.onc.1209852
Romano S, Mallardo M, Chiurazzi F et al (2008) The effect of FK506 on transforming growth factor beta signaling and apoptosis in chronic lymphocytic leukemia B cells. Haematologica 93:1039–1048. doi:10.3324/haematol.12402
Zhang Y, Adachi M, Kawamura R, Imai K (2006) Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ 13:125–140
Zhang Y, Adachi M, Kawamura R et al (2006) Bmf contributes to histone deacetylase inhibitor-mediated enhancing effects on apoptosis after ionizing radiation. Apoptosis 11:1349–1357
Fernandez Y, Verhaegen M, Miller TP et al (2005) Differential regulation of noxa in normal melanocytes and melanoma cells by proteasome inhibition: therapeutic implications. Cancer Res 65:6294–6304. doi:10.1158/0008-5472.CAN-05-0686
Qin JZ, Ziffra J, Stennett L et al (2005) Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res 65:6282–6293. doi:10.1158/0008-5472.CAN-05-0676
Nikiforov MA, Riblett M, Tang WH et al (2007) Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proc Natl Acad Sci USA 104:19488–19493. doi:10.1073/pnas.0708380104
Qin JZ, Stennett L, Bacon P et al (2004) p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas. Mol Cancer Ther 3:895–902
Nefedova Y, Sullivan DM, Bolick SC, Dalton WS, Gabrilovich DI (2008) Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood 111:2220–2229. doi:10.1182/blood-2007-07-102632
Dias N, Stein CA (2002) Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther 1:347–355
Vidal L, Blagden S, Attard G, de Bono J (2005) Making sense of antisense. Eur J Cancer 41:2812–2818. doi:10.1016/j.ejca.2005.06.029
Kim R, Emi M, Matsuura K, Tanabe K (2007) Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy. Cancer Gene Ther 14:1–11. doi:10.1038/sj.cgt.7700986
Pellecchia M, Reed JC (2004) Inhibition of anti-apoptotic Bcl-2 family proteins by natural polyphenols: new avenues for cancer chemoprevention and chemotherapy. Curr Pharm Des 10:1387–1398. doi:10.2174/1381612043384880
Chan SL, Lee MC, Tan KO et al (2003) Identification of chelerythrine as an inhibitor of BclXL function. J Biol Chem 278:20453–20456. doi:10.1074/jbc.C300138200
Becattini B, Kitada S, Leone M et al (2004) Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L). Chem Biol 11:389–395. doi:10.1016/j.chembiol.2004.02.020
Tzung SP, Kim KM, Basanez G et al (2001) Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat Cell Biol 3:183–191. doi:10.1038/35055095
Leone M, Zhai D, Sareth S, Kitada S, Reed JC, Pellecchia M (2003) Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res 63:8118–8121
Wang JL, Liu D, Zhang ZJ et al (2000) Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA 97:7124–7129. doi:10.1073/pnas.97.13.7124
Degterev A, Lugovskoy A, Cardone M et al (2001) Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol 3:173–182. doi:10.1038/35055085
van Delft MF, Wei AH, Mason KD et al (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10:389–399. doi:10.1016/j.ccr.2006.08.027
Wang G, Nikolovska-Coleska Z, Yang CY et al (2006) Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem 49:6139–6142. doi:10.1021/jm060460o
Verhaegen M, Bauer JA, Martin de la Vega C et al (2006) A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species. Cancer Res 66:11348–11359. doi:10.1158/0008-5472.CAN-06-1748
Nguyen M, Marcellus RC, Roulston A et al (2007) Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 104:19512–19517. doi:10.1073/pnas.0709443104
Konopleva M, Watt J, Contractor R et al (2008) Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res 68:3413–3420. doi:10.1158/0008-5472.CAN-07-1919
Campas C, Cosialls AM, Barragan M et al (2006) Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp Hematol 34:1663–1669. doi:10.1016/j.exphem.2006.07.008
Mott JL, Bronk SF, Mesa RA, Kaufmann SH, Gores GJ (2008) BH3-only protein mimetic obatoclax sensitizes cholangiocarcinoma cells to Apo2L/TRAIL-induced apoptosis. Mol Cancer Ther 7:2339–2347. doi:10.1158/1535-7163.MCT-08-0285
Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D (2007) The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood 109:4441–4449. doi:10.1182/blood-2006-07-034173
Witters LM, Witkoski A, Planas-Silva MD, Berger M, Viallet J, Lipton A (2007) Synergistic inhibition of breast cancer cell lines with a dual inhibitor of EGFR-HER-2/neu and a Bcl-2 inhibitor. Oncol Rep 17:465–469
Li J, Viallet J, Haura EB (2008) A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells. Cancer Chemother Pharmacol 61:525–534. doi:10.1007/s00280-007-0499-3
Labi V, Grespi F, Baumgartner F, Villunger A (2008) Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy? Cell Death Differ 15:977–987
Oltersdorf T, Elmore SW, Shoemaker AR et al (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681. doi:10.1038/nature03579
Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A (2007) Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 117:112–121. doi:10.1172/JCI28281
Konopleva M, Contractor R, Tsao T et al (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10:375–388. doi:10.1016/j.ccr.2006.10.006
Tse C, Shoemaker AR, Adickes J et al (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68:3421–3428. doi:10.1158/0008-5472.CAN-07-5836
Acknowledgments
The work in our laboratories is supported by fellowships and grants from the Austrian Science Fund (FWF): Y212-B13 START, the Doctoral College MCBO, the SFB021, the Association for International Cancer Research (AICR), EU-FP7 (ApopTrain) and the Tyrolean Science Fund (TWF). We apologize to the many scientists in this field whose excellent research was not cited but was only referred to indirectly through reviews. The authors have no competing financial interest.
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Frenzel, A., Grespi, F., Chmelewskij, W. et al. Bcl2 family proteins in carcinogenesis and the treatment of cancer. Apoptosis 14, 584–596 (2009). https://doi.org/10.1007/s10495-008-0300-z
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DOI: https://doi.org/10.1007/s10495-008-0300-z