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• W1994705026 abstract "Histone deacetylase activity is potently inhibited by hydroaximc acid derivatives such as suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). These inhibitors specifically induce differentiation/apoptosis of transformed cellsin vitro and suppress tumor growth in vivo. Because of its low toxicity, SAHA is currently evaluated in clinical trials for the treatment of cancer. SAHA and TSA induce apoptosis, which is characterized by mitochondrial stress, but so far, the critical elements of this apoptotic program remain poorly defined. To characterize in more detail this apoptotic program, we used human cell lines containing alterations in important elements of apoptotic response such as: p53, Bcl-2, caspase-9, and caspase-3. We demonstrate that caspase-9 is critical for apoptosis induced by SAHA and TSA and that efficient proteolytic activation of caspase-2, caspase-8, and caspase-7 strictly depends on caspase-9. Bcl-2 efficiently antagonizes cytochrome c release and apoptosis in response to both histone deacetylase inhibitors. We provide evidences that translocation into the mitochondria of the Bcl-2 family member Bid depends on caspase-9 and that this translocation is a late event during TSA-induced apoptosis. We also demonstrate that the susceptibility to TSA- and SAHA-induced cell death is regulated by p53. Histone deacetylase activity is potently inhibited by hydroaximc acid derivatives such as suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). These inhibitors specifically induce differentiation/apoptosis of transformed cellsin vitro and suppress tumor growth in vivo. Because of its low toxicity, SAHA is currently evaluated in clinical trials for the treatment of cancer. SAHA and TSA induce apoptosis, which is characterized by mitochondrial stress, but so far, the critical elements of this apoptotic program remain poorly defined. To characterize in more detail this apoptotic program, we used human cell lines containing alterations in important elements of apoptotic response such as: p53, Bcl-2, caspase-9, and caspase-3. We demonstrate that caspase-9 is critical for apoptosis induced by SAHA and TSA and that efficient proteolytic activation of caspase-2, caspase-8, and caspase-7 strictly depends on caspase-9. Bcl-2 efficiently antagonizes cytochrome c release and apoptosis in response to both histone deacetylase inhibitors. We provide evidences that translocation into the mitochondria of the Bcl-2 family member Bid depends on caspase-9 and that this translocation is a late event during TSA-induced apoptosis. We also demonstrate that the susceptibility to TSA- and SAHA-induced cell death is regulated by p53. histone deacetylase wild type catalytic-inactive caspase-3 catalytic inactive caspase-3 WT caspase-9 dominant negative daunorubicin 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine histone deacetylase inhibitor green fluorescent protein p53 dominant negative polyADP-ribosyltransferase suberoylanilide hydroxamic acid trichostatin-A z-Val-Ala-Asp-fluoromethylketone neomycin tetramethylrhodamine isothiocyanate 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid adenovirus early region 1A Histone acetyl transferases and histone deacetylases (HDACs)1 are emerging as important components that affect the dynamics of chromatin folding during gene transcription (1Narlikar G.J. Fan H.Y. Kingston R.E. Cell. 2002; 108: 475-487Google Scholar). HDACs catalyze the hydrolyisis of acetyl groups from amino-terminal lysine residues of the nucleosomal core histones (1Narlikar G.J. Fan H.Y. Kingston R.E. Cell. 2002; 108: 475-487Google Scholar, 2Fischle W. Kiermer V. Dequiedt F. Verdin E. Biochem. Cell Biol. 2001; 79: 337-348Google Scholar). Histone deacetylases inhibitors (HDIs) are promising agents for anticancer therapy; they exhibit strong antitumor activities in vivo with low toxicity in preclinical studies.HADC inhibitors belong to a heterogenous class of compounds that includes derivatives of short chain fatty acids, hydroxamic acids, cyclic tetrapetides, and benzamides. Among the hydroxamic acids, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) are commonly used inhibitors of HDACs (3Melnick A. Licht J.D. Curr. Opin. Hematol. 2002; 9: 322-332Google Scholar, 4Marks P.A. Rifkind R.A. Richon V.M. Breslow R. Miller T. Kelly W.K. Nat. Rev. Cancer. 2001; 1: 194-202Google Scholar).Numerous anti-proliferative effects have been reported for TSA and SAHA, including induction of G0/G2 cell cycle arrest, differentiation, and selective apoptosis of transformed cells (5Medina V. Edmonds B. Young G.P. James R. Appleton S. Zalewski P.D. Cancer Res. 1997; 57: 3697-3707Google Scholar, 6Richon V.M. Emiliani S. Verdin E. Webb Y. Breslow R. Rifkind R.A. Marks P.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3003-3007Google Scholar, 7Wang J. Saunthararajah Y. Redner R.L. Liu J.M. Cancer Res. 1999; 59: 2766-2769Google Scholar, 8Butler L.M. Agus D.B. Scher H.I. Higgins B. Rose A. Cordon-Cardo C. Thaler H.T. Rifkind R.A. Marks P.A. Richon V.M. Cancer Res. 2000; 60: 5165-5170Google Scholar). SAHA, in particular, shows strong anti-proliferative effects but low toxicity in vivo and is currently under clinical trials for the treatment of solid and hematological tumors (3Melnick A. Licht J.D. Curr. Opin. Hematol. 2002; 9: 322-332Google Scholar, 4Marks P.A. Rifkind R.A. Richon V.M. Breslow R. Miller T. Kelly W.K. Nat. Rev. Cancer. 2001; 1: 194-202Google Scholar).The cystein proteases, which belong to the family of caspases, play a critical role in the apoptotic response (9Shi Y. Mol. Cell. 2002; 9: 459-470Google Scholar, 10Cryns V. Yuan J. Genes Dev. 1998; 12: 1551-1570Google Scholar, 11Thornberry N.A. Lazebnik Y. Science. 1998; 281: 1312-1316Google Scholar). Several anticancer drugs exert their antineoplastic activity by inducing tumor cell apoptosis. Various of these antitumor drugs trigger mitochondrial stress that can lead to apoptosome-mediated caspase-9 activation. Caspase-9 activates the effectors caspase-3 and -7, which then trigger cell fragmentation by cleaving selected death substrates and also process different caspases, thus leading to the generation of the amplification loop (12Adrain C. Martin S.J. Trends Biochem. Sci. 2001; 26: 390-397Google Scholar, 13Wang X. Genes Dev. 2001; 15: 2922-2933Google Scholar).An alternative apoptotic pathway is triggered by the cell surface death receptor (extrinsic pathway), which includes caspase-8 and caspase-10 as apical caspases (10Cryns V. Yuan J. Genes Dev. 1998; 12: 1551-1570Google Scholar, 11Thornberry N.A. Lazebnik Y. Science. 1998; 281: 1312-1316Google Scholar, 14Nagata S. Annu. Rev. Genet. 1999; 33: 29-55Google Scholar). However by cleaving Bid, a Bcl-2 family member, these caspases can induce mitochondria permeabilization and activation of the amplifier function of the apoptosome (15Bouillet P. Strasser A. J. Cell Sci. 2002; 115: 1567-1574Google Scholar).Chemoresistance is frequently caused by aberrant apoptosis that in some instances has been related to defects in caspase activation (16Soengas M.S. Capodieci P. Polsky D. Mora J. Esteller M. Opitz-Araya X. McCombie R. Herman J.G. Gerald W.L. Lazebnik Y.A. Cordon-Cardo C. Lowe S.W. Nature. 2001; 409: 207-211Google Scholar, 17Liu J.R. Opipari A.W. Tan L. Jiang Y. Zhang Y. Tang H. Nunez G. Cancer Res. 2002; 62: 924-931Google Scholar). Therefore, the definition of the apoptotic pathway that is induced by a particular anticancer drug is important to design therapeutic trials and clinical treatment.The mechanism of HDI-induced apoptosis has only been marginally addressed. The role of the tumor suppressor p53 in the HDI-triggered apoptosis is not clear. Some reports have suggested an effect of p53 in this apoptotic response (18Sambucetti L.C. Fischer D.D. Zabludoff S. Kwon P.O. Chamberlin H. Trogani N. Xu H. Cohen D. J. Biol. Chem. 1999; 274: 34940-34947Google Scholar, 19Juan L.J. Shia W.J. Chen M.H. Yang W.M. Seto E. Lin Y.S. Wu C.W. J. Biol. Chem. 2000; 275: 20436-20443Google Scholar, 20Kim M.S. Kwon H.J. Lee Y.M. Baek J.H. Jang J.E. Lee S.W. Moon E.J. Kim H.S. Lee S.K. Chung H.Y. Kim C.W. Kim K.W. Nat. Med. 2001; 7: 437-443Google Scholar, 21Ito A. Kawaguchi Y. Lai C.H. Kovacs J.J. Higashimoto Y. Appella E. Yao T.P. EMBO J. 2002; 21: 6236-6245Google Scholar), whereas other studies have pointed to a p53-independent apoptotic response (22Vrana J.A. Decker R.H. Johnson C.R. Wang Z. Jarvis W.D. Richon V.M. Ehinger M. Fisher P.B. Grant S. Oncogene. 1999; 18: 7016-7025Google Scholar, 23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar, 24Zhu W.G. Lakshmanan R.R. Beal M.D. Otterson G.A. Cancer Res. 2001; 61: 1327-1333Google Scholar). Mitochondrial stress and release of cytochrome c mark the apoptotic response to HDIs (5Medina V. Edmonds B. Young G.P. James R. Appleton S. Zalewski P.D. Cancer Res. 1997; 57: 3697-3707Google Scholar, 23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar, 24Zhu W.G. Lakshmanan R.R. Beal M.D. Otterson G.A. Cancer Res. 2001; 61: 1327-1333Google Scholar, 26Herold C. Ganslmayer M. Ocker M. Hermann M. Geerts A. Hahn E.G. Schuppan D. J. Hepatol. 2002; 36: 233-240Google Scholar), and changes in the expression of Bcl-2 family members such as Bcl-2, Bax, or Bad have been detected in some cell lines (26Herold C. Ganslmayer M. Ocker M. Hermann M. Geerts A. Hahn E.G. Schuppan D. J. Hepatol. 2002; 36: 233-240Google Scholar, 27Sawa H. Murakami H. Ohshima Y. Sugino T. Nakajyo T. Kisanuki T. Tamura Y. Satone A. Ide W. Hashimoto I. Kamada H. Brain Tumor Pathol. 2001; 18: 109-114Google Scholar). Caspase-3 activation was reported by different studies (5Medina V. Edmonds B. Young G.P. James R. Appleton S. Zalewski P.D. Cancer Res. 1997; 57: 3697-3707Google Scholar, 23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar, 24Zhu W.G. Lakshmanan R.R. Beal M.D. Otterson G.A. Cancer Res. 2001; 61: 1327-1333Google Scholar, 26Herold C. Ganslmayer M. Ocker M. Hermann M. Geerts A. Hahn E.G. Schuppan D. J. Hepatol. 2002; 36: 233-240Google Scholar), but cell death after SAHA treatment was observed also in the presence of pancaspase inhibitor zVAD-fmk (23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar). However, the same study suggested that a caspase not efficiently inhibited by zVAD-fmk could be involved in transducing the apoptotic signal triggered by SAHA (23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar).Our work was designed to identify the critical elements involved in transducing HDI-induced apoptotic signals. Human cell lines containing known mutations in key elements of the apoptotic pathway allowed us to elucidate caspase-9 requirements in the apoptotic response to HDIs. We show that HDI-induced proteolytic activation of caspase-2, caspase-8, and caspase-7 was strictly dependent on caspase-9. Moreover, HDIs provoke, late during apoptosis, translocation of the Bcl-2 family member Bid into the mitochondria, and this translocation also depends on caspase-9. We also show that Bcl-2 efficiently antagonizes cytochrome c release and apoptosis in response to TSA. Finally, we demonstrate that the susceptibility to cell death in response to TSA and SAHA treatment is regulated by p53.DISCUSSIONThe definition of the apoptotic pathway triggered by an anti-cancer drug is important to predict the efficacy of a particular chemotherapeutic treatment including that agent. The HDIs are promising anticancer drugs as they selectively induce differentiation and cell death of transformed cells, and some of them are now under clinical trials for both solid and hematological tumors (3Melnick A. Licht J.D. Curr. Opin. Hematol. 2002; 9: 322-332Google Scholar, 4Marks P.A. Rifkind R.A. Richon V.M. Breslow R. Miller T. Kelly W.K. Nat. Rev. Cancer. 2001; 1: 194-202Google Scholar, 6Richon V.M. Emiliani S. Verdin E. Webb Y. Breslow R. Rifkind R.A. Marks P.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3003-3007Google Scholar).The selectivity of HDIs toward transformed cells as compared with untransformed normal cells has been confirmed by our work. We provide evidence that a single oncogenic lesion, such as EIA expression, renders IMR90 fibroblasts highly susceptible to cell death when grown in the presence of SAHA or TSA. We have also confirmed that mitochondria play a central role during HDI-mediated apoptotic response (5Medina V. Edmonds B. Young G.P. James R. Appleton S. Zalewski P.D. Cancer Res. 1997; 57: 3697-3707Google Scholar, 23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar, 24Zhu W.G. Lakshmanan R.R. Beal M.D. Otterson G.A. Cancer Res. 2001; 61: 1327-1333Google Scholar, 26Herold C. Ganslmayer M. Ocker M. Hermann M. Geerts A. Hahn E.G. Schuppan D. J. Hepatol. 2002; 36: 233-240Google Scholar). In addition, our data demonstrate that the initiator caspase-9 is critical for this cell death pathway. In IMR90-E1A and in MCF-7 cells, abrogation of caspase-9 activity suppressed apoptosis in response to TSA or SAHA and blocked processing of PARP, caspase-2, -7, and -8.TSA- and SAHA-induced processing of Bid and subsequent translocation to mitochondria were also dependent on caspase-9. These data suggest that Bid could play a role in the amplification loop rather than during the initial phase of the process in HDI-induced cell death. A late function of Bid is supported by the time-lapse analysis. Translocation of Bid to mitochondria was observed in vivo during TSA-induced cell death after 46.17 (±25.01) min from the appearance of the first signs of cell death (cell shrinkage and membrane blebbing). A previous study suggested that a caspase not efficiently inhibited by zVAD-fmk could be responsible for Bid cleavage in response to SAHA (23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar). The current study supports the notion that this caspase is caspase-9 or a caspase regulated by caspase-9.Our findings do not exclude a role for the initiator caspase-2 and -8 upstream of caspase-9 during HDI-induced cell death. We used proenzyme cleavage as marker of caspase-2 and -8 activation. However, regulative caspases might also be activated in the absence of proteolytic processing (44Stennicke H.R. Deveraux Q.L. Humke E.W. Reed J.C. Dixit V.M. Salvesen G.S. J. Biol. Chem. 1999; 274: 8359-8362Google Scholar). Recent studies have showed that caspase-2 can be activated independently from proteolytic processing (45Read S.H. Baliga B.C. Ekert P.G. Vaux D.L. Kumar S. J. Cell Biol. 2002; 159: 739-745Google Scholar), and therefore, further investigations are needed to assess whether caspase-2 plays a role as regulator of the mitochondrial integrity (28Paroni G. Henderson C. Schneider C. Brancolini C. J. Biol. Chem. 2002; 277: 15147-15161Google Scholar,46Lassus P. Opitz-Araya X. Lazebnik Y. Science. 2002; 297: 1352-1354Google Scholar, 47Robertson J.D. Enoksson M. Suomela M. Zhivotovsky B. Orrenius S. J. Biol. Chem. 2002; 277: 29803-29809Google Scholar, 48Guo Y. Srinivasula S.M. Druilhe A. Fernandes-Alnemri T. Alnemri E.S. J. Biol. Chem. 2002; 277: 13430-13437Google Scholar), upstream of caspase-9 during apoptosis induced by HDIs. Concerning caspase-8, a critical role of this initiator caspase during HDI-induced cell death should be excluded since it has been reported that its inhibition, through expression of the cowpox virus protein CrmA, did not affect SAHA-induced cell death (23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar).We demonstrate that p53 is essential for an efficient apoptotic response to TSA and SAHA treatments. The role of p53 has been investigated by using primary human fibroblasts transformed with E1A and Ha-Ras-V12 where p53 was inactivated by ectopic expression MDM2 or p53DN mutant (42Seger Y.R. Garcia-Cao M. Piccinin S. Cunsolo C.L. Doglioni C. Blasco M.A. Hannon G.J. Maestro R. Cancer Cell. 2002; 2: 401-413Google Scholar). Our data are in disagreement with a previous report, which suggested the existence of a p53-independent apoptotic pathway in response to SAHA (23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar). Indeed, although we find that p53 does affect the rate of HDI-induced cell death, prolonged treatments with these inhibitors can also induce a p53-independent response. It is thus likely that such a delayed p53-independent response was the one described previously (23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar).Moreover, it has also been reported that conditional expression of p53 failed to modify the apoptotic response to SAHA in U937 cells (22Vrana J.A. Decker R.H. Johnson C.R. Wang Z. Jarvis W.D. Richon V.M. Ehinger M. Fisher P.B. Grant S. Oncogene. 1999; 18: 7016-7025Google Scholar). U937 cells do not express p73 (51Stiewe T. Putzer B.M. Nat. Genet. 2000; 26: 464-469Google Scholar), and it is known that the p53 family members p63 and p73 can modulate the p53 apoptotic response (49Zacchi P. Gostissa M. Uchida T. Salvagno C. Avolio F. Volinia S. Ronai Z. Blandino G. Schneider C. Del Sal G. Nature. 2002; 419: 853-857Google Scholar, 50Flores E.R. Tsai K.Y. Crowley D. Sengupta S. Yang A. McKeon F. Jacks T. Nature. 2002; 416: 560-564Google Scholar). In fact, the combined loss of p63 and p73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage (50Flores E.R. Tsai K.Y. Crowley D. Sengupta S. Yang A. McKeon F. Jacks T. Nature. 2002; 416: 560-564Google Scholar). Therefore, the absence of p73 expression might account for the inability of these cells to mount a p53-dependent apoptosis in response to SAHA (22Vrana J.A. Decker R.H. Johnson C.R. Wang Z. Jarvis W.D. Richon V.M. Ehinger M. Fisher P.B. Grant S. Oncogene. 1999; 18: 7016-7025Google Scholar).A differential behavior was noted for TSA- and SAHA-induced apoptosis relative to the rate of the dependence from p53. Cells lacking functional p53 were still resistant to cell death after long term treatments with SAHA (48 h), whereas apoptosis was induced in the same cells after long term treatments with TSA. One could postulate that since TSA is an inhibitor of HDACs at nanomolar range, whereas SAHA is efficient at micromolar range (3Melnick A. Licht J.D. Curr. Opin. Hematol. 2002; 9: 322-332Google Scholar), this difference could mirror the potency of the two HDIs. In fact, we observed that histone H3 acetylation was more pronounced in cells treated with TSA.Several models could be proposed for the relationship between HDIs and p53. It has been reported that TSA up-regulates p53 in endothelial cells (20Kim M.S. Kwon H.J. Lee Y.M. Baek J.H. Jang J.E. Lee S.W. Moon E.J. Kim H.S. Lee S.K. Chung H.Y. Kim C.W. Kim K.W. Nat. Med. 2001; 7: 437-443Google Scholar), whereas HDAC1 can regulate p53 deacetylation, thereby reducing its transcriptional activity by targeting it for degradation (19Juan L.J. Shia W.J. Chen M.H. Yang W.M. Seto E. Lin Y.S. Wu C.W. J. Biol. Chem. 2000; 275: 20436-20443Google Scholar, 21Ito A. Kawaguchi Y. Lai C.H. Kovacs J.J. Higashimoto Y. Appella E. Yao T.P. EMBO J. 2002; 21: 6236-6245Google Scholar). Therefore, TSA and SAHA might activate p53, thus inducing the expression of p53 target genes involved in apoptosis. Array analysis of gene expression in our cellular system will allow us to better define the mechanism through which p53 regulates the apoptotic susceptibility to HDIs.Interestingly, production of reactive oxygen species is crucial for cell death induced by SAHA (23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar, 25Butler L.M. Zhou X. Xu W.S. Scher H.I. Rifkind R.A. Marks P.A. Richon V.M. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11700-11705Google Scholar), and transcription of redox-related genes, formation of reactive oxigen species, and oxidative degradation of mitochondria components have been suggested to be critical for a p53-dependent apoptosis (43Polyak K. Xia Y. Zweier J.L. Kinzler K.W. Vogelstein B. Nature. 1997; 389: 300-305Google Scholar). As schematized in Fig.7, we propose a model where the pattern of genes affected by TSA and SAHA can be influenced by the presence of p53 (directly or indirectly), and these genes can regulate the rate of cell death (apoptotic threshold).In conclusion, our findings support the notion that HDI-induced apoptosis requires caspase-9 activation through the release of cytochrome c in a Bcl-2-dependent and p53-sensitive manner. This pathway seems to be common to other anticancer-treatments; however, one difference can be noted when TSA is compared with the DNA-damaging agent daunorubicin in cells lacking caspase-3 activity. Bid, PARP, caspase-2, and -8 processing can still occur in MCF-7/C3CI cells treated with TSA. This suggests that HDIs could effect the rate of caspase activation even when the amplification loop, which is largely based on caspase-3, is defective. Definition of the molecular events that permit overcoming the caspase-3 defect is an interesting question that requires further work. Histone acetyl transferases and histone deacetylases (HDACs)1 are emerging as important components that affect the dynamics of chromatin folding during gene transcription (1Narlikar G.J. Fan H.Y. Kingston R.E. Cell. 2002; 108: 475-487Google Scholar). HDACs catalyze the hydrolyisis of acetyl groups from amino-terminal lysine residues of the nucleosomal core histones (1Narlikar G.J. Fan H.Y. Kingston R.E. Cell. 2002; 108: 475-487Google Scholar, 2Fischle W. Kiermer V. Dequiedt F. Verdin E. Biochem. Cell Biol. 2001; 79: 337-348Google Scholar). Histone deacetylases inhibitors (HDIs) are promising agents for anticancer therapy; they exhibit strong antitumor activities in vivo with low toxicity in preclinical studies. HADC inhibitors belong to a heterogenous class of compounds that includes derivatives of short chain fatty acids, hydroxamic acids, cyclic tetrapetides, and benzamides. Among the hydroxamic acids, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) are commonly used inhibitors of HDACs (3Melnick A. Licht J.D. Curr. Opin. Hematol. 2002; 9: 322-332Google Scholar, 4Marks P.A. Rifkind R.A. Richon V.M. Breslow R. Miller T. Kelly W.K. Nat. Rev. Cancer. 2001; 1: 194-202Google Scholar). Numerous anti-proliferative effects have been reported for TSA and SAHA, including induction of G0/G2 cell cycle arrest, differentiation, and selective apoptosis of transformed cells (5Medina V. Edmonds B. Young G.P. James R. Appleton S. Zalewski P.D. Cancer Res. 1997; 57: 3697-3707Google Scholar, 6Richon V.M. Emiliani S. Verdin E. Webb Y. Breslow R. Rifkind R.A. Marks P.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3003-3007Google Scholar, 7Wang J. Saunthararajah Y. Redner R.L. Liu J.M. Cancer Res. 1999; 59: 2766-2769Google Scholar, 8Butler L.M. Agus D.B. Scher H.I. Higgins B. Rose A. Cordon-Cardo C. Thaler H.T. Rifkind R.A. Marks P.A. Richon V.M. Cancer Res. 2000; 60: 5165-5170Google Scholar). SAHA, in particular, shows strong anti-proliferative effects but low toxicity in vivo and is currently under clinical trials for the treatment of solid and hematological tumors (3Melnick A. Licht J.D. Curr. Opin. Hematol. 2002; 9: 322-332Google Scholar, 4Marks P.A. Rifkind R.A. Richon V.M. Breslow R. Miller T. Kelly W.K. Nat. Rev. Cancer. 2001; 1: 194-202Google Scholar). The cystein proteases, which belong to the family of caspases, play a critical role in the apoptotic response (9Shi Y. Mol. Cell. 2002; 9: 459-470Google Scholar, 10Cryns V. Yuan J. Genes Dev. 1998; 12: 1551-1570Google Scholar, 11Thornberry N.A. Lazebnik Y. Science. 1998; 281: 1312-1316Google Scholar). Several anticancer drugs exert their antineoplastic activity by inducing tumor cell apoptosis. Various of these antitumor drugs trigger mitochondrial stress that can lead to apoptosome-mediated caspase-9 activation. Caspase-9 activates the effectors caspase-3 and -7, which then trigger cell fragmentation by cleaving selected death substrates and also process different caspases, thus leading to the generation of the amplification loop (12Adrain C. Martin S.J. Trends Biochem. Sci. 2001; 26: 390-397Google Scholar, 13Wang X. Genes Dev. 2001; 15: 2922-2933Google Scholar). An alternative apoptotic pathway is triggered by the cell surface death receptor (extrinsic pathway), which includes caspase-8 and caspase-10 as apical caspases (10Cryns V. Yuan J. Genes Dev. 1998; 12: 1551-1570Google Scholar, 11Thornberry N.A. Lazebnik Y. Science. 1998; 281: 1312-1316Google Scholar, 14Nagata S. Annu. Rev. Genet. 1999; 33: 29-55Google Scholar). However by cleaving Bid, a Bcl-2 family member, these caspases can induce mitochondria permeabilization and activation of the amplifier function of the apoptosome (15Bouillet P. Strasser A. J. Cell Sci. 2002; 115: 1567-1574Google Scholar). Chemoresistance is frequently caused by aberrant apoptosis that in some instances has been related to defects in caspase activation (16Soengas M.S. Capodieci P. Polsky D. Mora J. Esteller M. Opitz-Araya X. McCombie R. Herman J.G. Gerald W.L. Lazebnik Y.A. Cordon-Cardo C. Lowe S.W. Nature. 2001; 409: 207-211Google Scholar, 17Liu J.R. Opipari A.W. Tan L. Jiang Y. Zhang Y. Tang H. Nunez G. Cancer Res. 2002; 62: 924-931Google Scholar). Therefore, the definition of the apoptotic pathway that is induced by a particular anticancer drug is important to design therapeutic trials and clinical treatment. The mechanism of HDI-induced apoptosis has only been marginally addressed. The role of the tumor suppressor p53 in the HDI-triggered apoptosis is not clear. Some reports have suggested an effect of p53 in this apoptotic response (18Sambucetti L.C. Fischer D.D. Zabludoff S. Kwon P.O. Chamberlin H. Trogani N. Xu H. Cohen D. J. Biol. Chem. 1999; 274: 34940-34947Google Scholar, 19Juan L.J. Shia W.J. Chen M.H. Yang W.M. Seto E. Lin Y.S. Wu C.W. J. Biol. Chem. 2000; 275: 20436-20443Google Scholar, 20Kim M.S. Kwon H.J. Lee Y.M. Baek J.H. Jang J.E. Lee S.W. Moon E.J. Kim H.S. Lee S.K. Chung H.Y. Kim C.W. Kim K.W. Nat. Med. 2001; 7: 437-443Google Scholar, 21Ito A. Kawaguchi Y. Lai C.H. Kovacs J.J. Higashimoto Y. Appella E. Yao T.P. EMBO J. 2002; 21: 6236-6245Google Scholar), whereas other studies have pointed to a p53-independent apoptotic response (22Vrana J.A. Decker R.H. Johnson C.R. Wang Z. Jarvis W.D. Richon V.M. Ehinger M. Fisher P.B. Grant S. Oncogene. 1999; 18: 7016-7025Google Scholar, 23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar, 24Zhu W.G. Lakshmanan R.R. Beal M.D. Otterson G.A. Cancer Res. 2001; 61: 1327-1333Google Scholar). Mitochondrial stress and release of cytochrome c mark the apoptotic response to HDIs (5Medina V. Edmonds B. Young G.P. James R. Appleton S. Zalewski P.D. Cancer Res. 1997; 57: 3697-3707Google Scholar, 23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar, 24Zhu W.G. Lakshmanan R.R. Beal M.D. Otterson G.A. Cancer Res. 2001; 61: 1327-1333Google Scholar, 26Herold C. Ganslmayer M. Ocker M. Hermann M. Geerts A. Hahn E.G. Schuppan D. J. Hepatol. 2002; 36: 233-240Google Scholar), and changes in the expression of Bcl-2 family members such as Bcl-2, Bax, or Bad have been detected in some cell lines (26Herold C. Ganslmayer M. Ocker M. Hermann M. Geerts A. Hahn E.G. Schuppan D. J. Hepatol. 2002; 36: 233-240Google Scholar, 27Sawa H. Murakami H. Ohshima Y. Sugino T. Nakajyo T. Kisanuki T. Tamura Y. Satone A. Ide W. Hashimoto I. Kamada H. Brain Tumor Pathol. 2001; 18: 109-114Google Scholar). Caspase-3 activation was reported by different studies (5Medina V. Edmonds B. Young G.P. James R. Appleton S. Zalewski P.D. Cancer Res. 1997; 57: 3697-3707Google Scholar, 23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar, 24Zhu W.G. Lakshmanan R.R. Beal M.D. Otterson G.A. Cancer Res. 2001; 61: 1327-1333Google Scholar, 26Herold C. Ganslmayer M. Ocker M. Hermann M. Geerts A. Hahn E.G. Schuppan D. J. Hepatol. 2002; 36: 233-240Google Scholar), but cell death after SAHA treatment was observed also in the presence of pancaspase inhibitor zVAD-fmk (23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10833-10838Google Scholar). However, the same study suggested that a caspase not efficiently inhibited by zVAD-fmk could be involved in transducing the apoptotic signal triggered by SAHA (23Ruefli A.A. Ausserlechner M.J. Bernhard D. Sutton V.R. Tainton K.M. Kofler R. Smyth M.J. Johnstone R.W. Proc. Natl. Aca" @default.
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