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Contents lists available at ScienceDirect

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Review

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Targeting apoptosis for anticancer therapy

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Simone Fulda ∗ Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528 Frankfurt, Germany

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Keywords: Apoptosis Cell death Cancer Death receptor Mitochondria

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1. Introduction

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Programmed cell death via apoptosis is characteristically disturbed in human cancers. This facilitates not only tumor formation and progression, but also treatment resistance. Since many currently applied anticancer treatment strategies rely on intact cell death signaling pathways for their therapeutic efficacy, a better understanding of the regulatory mechanisms that control cell death signaling pathways is critical to bypass resistance. Thus, reactivation of cell death programs in cancer cells may open new perspectives for more effective and more tumor-selective, yet less toxic anticancer therapies. © 2014 Published by Elsevier Ltd.

Programmed cell death is a fundamental cellular program that is inherent in every cell of the human body [1]. Apoptosis represents one of the most extensively studied forms of programmed cell death that plays a critical role during various physiological processes as well as in a variety of pathological conditions [1]. Against the background that tissue homeostasis is maintained by a subtle balance between cell death on one side and cell proliferation on the other side, any changes in one of these parameters can form the basis for human diseases. The fact that under normal conditions apoptosis represents a safeguard mechanism to prevent tumorigenesis implies that evasion of apoptosis constitutes a characteristic feature of human cancers [2]. Too little cell death not only contributes to cancer formation, but also to cancer progression and treatment resistance [3]. A better understanding of the mechanisms that are involved in the regulation of apoptosis and their dysregulation in human cancers is expected to provide novel opportunities for exploiting this cellular program for cancer therapy.

2. Apoptosis programs Two principal apoptosis signal transduction pathways have been delineated that constitute the basic machinery for triggering apoptosis in mammalian cells [4]. First, the death receptor (extrinsic) pathway links signals from the exterior of the cell into the intracellular signal transduction machinery to engage apoptosis [5]. Cell surface receptors of the death receptor family are integrated

∗ Tel.: +49 69 67866557; fax: +49 69 6786659157. E-mail address: [email protected]

into the plasma membrane and become activated upon ligation by their cognate ligands. Death receptors comprise CD95 (Fas/Apo1), Tumor-Necrosis-Factor-related apoptosis-inducing ligand (TRAIL) receptors as well as tumor necrosis factor (TNF) receptor [5]. Corresponding death receptor ligands are CD95 ligand, TRAIL and TNF␣ [5]. Ligation of death receptors by their ligands leads to oligomerization of death receptors followed by the recruitment of adaptor molecules to the intracellular part of death receptors. This results in the formation of a multimeric protein complex at the plasma membrane, the so-called death-inducing signaling complex (DISC), that drives activation of caspase-8. Once activated, caspase-8 can either directly cleave downstream effector caspases such as caspase-3 or can indirectly initiate activation of the mitochondrial (intrinsic) pathway of apoptosis via proteolytic cleavage of Bid into tBid. tBid in turn translocates to mitochondrial membranes to initiate mitochondrial outer membrane permeabilization, e.g. via interaction with other Bcl-2 family proteins on mitochondrial membranes (Fig. 1). Q2 Within the mitochondrial (intrinsic) pathway of apoptosis, apoptotic stimuli trigger the release of mitochondrial intermembrane space proteins including cytochrome c and second mitochondria-derived activator of caspases (Smac) into the cytosol [6]. Cytochrome c promotes activation of caspases by forming a protein complex composed of cytochrome c, Apaf-1 and caspase-9, leading to caspase-9 and subsequently caspase-3 activation. Smac facilitates apoptosis by neutralizing Inhibitor of Apoptosis (IAP) proteins [6]. This Smac mimetic-mediated inhibition of IAP proteins releases the brake on caspases resulting in caspase activation and eventually cell death. Signaling to apoptosis is tightly regulated at various levels to ensure that this program is not accidentally activated, as inappropriate engagement of apoptosis programs imposes a serious threat to the cell’s survival. These physiological restraints

http://dx.doi.org/10.1016/j.semcancer.2014.05.002 1044-579X/© 2014 Published by Elsevier Ltd.

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TRAIL TRAIL-R1/2 Ab Aza, IFNs, retinoic acid ABT-737, ABT-199

TRAIL-R

TRAIL

Caspase-8

cFLIP

mTORi, HDACi

Bcl-2 Caspase-3

Apoptosis Fig. 1. Examples of targeting apoptosis pathways for cancer therapy. The death receptor pathway can be targeted by engaging TRAIL receptors using TRAIL or TRAIL receptor 1 or 2 antibodies (TRAIL-R1/2 Ab), by restoring caspase-8 expression using 5-aza-2 -deoxycytidine (Aza), interferons (IFNs) or retinoic acid and by downregulating cFLIP using mTOR inhibitors (mTORi) or histone deacetylase (HDAC) inhibitors. The mitochondrial receptor pathway can be targeted by antagonizing antiapoptotic Bcl-2 family proteins using ABT-737 or ABT-199.

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on apoptosis signaling pathways have been abused by cancer cells in order to evade apoptosis. For example, various antiapoptotic factors are expressed at high levels in cancer cells and confer apoptosis resistance. Moreover, cancer cells have evolved mechanisms to inactivate proapoptotic molecules in order to escape the induction of apoptosis. In addition to caspasedependent apoptosis, also caspase-independent forms of apoptotic cell death exist. For example, apoptosis-inducing factor (AIF) and endonuclease G (ENDOG) were described as mitochondrial intermembrane proteins that cause large-scale DNA fragmentation independently of caspases upon their translocation to the nucleus [7,8]. 3. Therapeutic opportunities to exploit apoptosis for cancer therapy

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The elucidation of the molecular mechanisms that underlie the intrinsic apoptosis resistance of human cancers over the last decades has led to the identification of target structures that can be exploited for therapeutic purposes. The following paragraphs will focus on key target structures for the development of apoptosistargeted drugs.

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4. Target 1: death receptor pathway

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Signaling to apoptosis via the death receptor pathway can be disabled at various levels of the signal transduction cascade in human cancers. At the level of the plasma membrane, cell surface expression of death receptors can be impaired. Decreased surface expression of CD95 has been reported in drug-resistant variants of leukemia or neuroblastoma cells and has been connected to drug resistance [9]. In addition to CD95, alterations in TRAIL receptors have been implicated as a mechanism of resistance. This involves deficient transport of TRAIL receptors from intracellular stores toward the cell surface as well as deletions or mutations in genes encoding for the apoptosis-promoting TRAIL receptors TRAIL-R1 or -R2 [10–12]. Similarly, CD95 mutations were encountered, for example, in hematological malignancies [13,14]. In addition, aberrant expression of the decoy receptor TRAIL-R3 has been linked to apoptosis resistance, as the TRAIL system not only comprises proapoptotic TRAIL receptors that engage apoptosis, but also decoy receptors that are expressed at the cell surface, but do not transmit a death signal [15].

Apart from genetic causes, epigenetic mechanisms have frequently been shown to be involved in conferring apoptosis resistance. Epigenetic inactivation of key apoptosis regulatory proteins involves not only silencing of death receptors such as CD95 or TRAIL receptors but also epigenetic inactivation of key components of the intracellular signal transduction machinery that mediate death receptor signaling. One prominent example is epigenetic silencing of caspase-8, one of the initiator caspases that usually becomes activated upon formation of the DISC upon receptor ligation [16]. Silencing of caspase-8 has been reported in a variety of pediatric malignancies, including neuroblastoma, medulloblastoma, Ewing sarcoma and rhabdomyosarcoma in addition to small-cell lung carcinoma, and has been linked to evasion of apoptosis [17–21]. Another key regulator of death receptor signaling is cellular FLICE (FADD-like IL-1␤-converting enzyme)-inhibitory protein (cFLIP) that blocks apoptosis by interfering with the recruitment of caspase-8 to the DISC [22]. Overexpression of cFLIP has been implicated in conferring resistance to apoptosis induced by death receptor stimulation or by anticancer drugs in a variety of cancers [23,24]. Death receptors provide a suitable structure for targeted interference with apoptosis signaling pathways, since they contain as transmembrane receptors both an extracellular domain for binding of recombinant ligands or agonistic antibodies as well as an intracellular domain for interaction with signaling proteins. Recombinant death receptor ligands as well as therapeutic antibodies directed against death receptors have been developed in order to engage death receptors on the surface of cancer cells. Since ligation of TNFR1 by TNF␣ not only leads to the induction of cell death, but also provides an inflammatory signal, systemic administration of TNF␣ proved to be associated with severe toxicity [25]. Therefore, the exploitation of the TNF␣/TNFR1 system for cancer therapy has mainly been restricted to local administration of TNF␣, for example using isolated limb perfusion to deliver high doses of TNF␣ locoregionally [25]. By comparison, the TRAIL/TRAIL receptor system is considered as a promising representative of the death receptor family for cancer therapy, especially since TRAIL has been shown to preferentially trigger cell death in cancer cells compared to nonmalignant human cells. Pharmacokinetic and pharmacodynamic studies in non-human primates confirmed the safety of TRAIL administration even at relatively high concentrations [5]. TRAIL receptor agonists including recombinant TRAIL as well as humanized antibodies against the agonistic TRAIL receptors have been evaluated in early clinical trials both as single agents as well as in various combination regimens [26–29]. However, the clinical trials did not recapitulate the promising results obtained in preclinical in vivo models, which might be due to insufficient cross-linking of TRAIL receptors by the available TRAIL agonists. Preclinical studies have also demonstrated the requirement of rationally designed TRAIL-based combination therapies in order to maximize the antitumor activity of TRAIL. To this end, various combinations have been developed, including conventional chemotherapeutics, radiotherapy and targeted signal transduction modulators. The synergistic interaction of TRAIL receptor agonists together with DNA-damaging therapeutics, including DNA-damaging drugs or radiotherapy, has been linked to the upregulation of TRAIL receptors in response to DNA damage [30,31]. In addition, enhanced assembly of the TRAIL DISC upon DNA damage has been proposed to confer increased sensitivity in TRAILbased combination regimens [32]. Also, modulation of pro- and antiapoptotic signaling molecules in response to DNA-damaging agents may account for the increased apoptosis sensitivity by changing the ratio of pro- versus antiapoptotic factors in favor of apoptosis [4].

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protein Bax have been reported in human cancers. For example, single nucleotide substitution of the Bax gene or frameshift mutations have been described in hematopoietic neoplasms or colon carcinoma [44,45]. Furthermore, homozygous deletions of the BH3only protein Bim were encountered in mantle cell lymphoma [46]. In addition to these genetic changes, aberrant signaling via prosurvival pathways such as the PI3K/Akt/mTOR or the Ras/MEK/ERK pathways have been implicated in the dysregulation of Bcl-2 family proteins via phosphorylation events that can, for example, alter their expression levels and/or activity. To give one example, aberrant signaling via PI3K/Akt/mTOR or Ras/MEK/ERK leads to phosphorylation of Bim, thereby targeting Bim for degradation in proteasomes [47]. Since antiapoptotic proteins of the Bcl-2 family, including Bcl-2, Bcl-xL and Mcl-1, play a critical role in disabling the mitochondrial pathway of apoptosis, these antiapoptotic Bcl-2 family proteins have gained a lot of attention for the development of mitochondriatargeted cancer therapeutics. To this end, structure-based, rational drug design has resulted in the development of small-molecule Bcl-2 inhibitors. ABT-737 represents one of the first-generation compounds that antagonize Bcl-2, Bcl-xL and Bcl-W [48]. Since ABT-737 does not target Mcl-1, it is not surprising that Mcl-1 turned out to be a critical factor regulating resistance versus sensitivity to ABT-737 [49,50]. Consistently, resistance to ABT-737 due to Mcl-1 overexpression was shown to be bypassed by the addition of compounds that antagonize or downregulate Mcl-1. These strategies included the use of cyclin-dependent kinase (CDK) inhibitors such as roscovitine, flavopiridol and seliciclib as well as proteasome inhibitors that cause accumulation of Noxa expression, which in turn neutralizes Mcl-1 [51–56]. In addition, sorafinib in combination with ABT-737 was described to efficiently induce apoptosis and to suppress tumor growth in preclinical in vitro and in vivo models of hepatocellular carcinoma by suppressing Mcl-1 levels [57]. Recently, ABT-199 has been developed as a selective inhibitor of Bcl-2 that elicits potent antitumor activity, but spares normal platelets [58]. ABT-199 was shown to suppress the growth of Bcl-2-dependent tumors in vitro and in vivo without causing thrombocytopenia, since it does not neutralize Bcl-xL which is critical for the survival of platelets [58]. Also, ABT-199 showed efficacy against an aggressive Bcl-2/Myc-driven mouse lymphoma without provoking thrombocytopenia [59]. Furthermore, ABT-199 was described to enhance the antitumor effects of the anti-estrogen tamoxifen in breast carcinoma, whereas it counteracted adverse effects such as tamoxifen-stimulated endometrial hyperplasia [60]. Moreover, ABT-199 exhibited activity against multiple myeloma as well as chronic lymphocytic leukemia [61,62]. Recently, ABT199 was shown to exert potent antileukemic activity against acute myeloid leukemia (AML) cell lines, primary patient samples and murine primary AML xenografts [63]. As far as myeloid malignancies are concerned, ABT-199 cooperated with the demethylating agent 5-azacytidine [64].

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However, there is also a dark side to TRAIL receptor signaling in human cancers. There is already an inbuilt dichotomy in the TRAIL system, as both agonistic TRAIL receptors (i.e. TRAIL-R1 and TRAILR2), and antagonistic TRAIL receptors (i.e. TRAIL-R3 and TRAIL-R4) exist. This implies that recombinant human TRAIL can elicit in principle both proapoptotic as well as apoptosis-inhibiting signals depending on the expression of these different TRAIL receptors on the cell surface. In addition, agonistic TRAIL receptors can not only signal to cell death, but can also engage cell survival pathways in a context-dependent manner, imposing an additional layer of complexity on the dichotomy of the TRAIL system. This dichotomy of the TRAIL system has obvious important implications for human cancers. For example, TRAIL has been reported to stimulate proliferation in TRAIL-resistant types of cancer [33]. Also, TRAIL-stimulated non-canonical kinase cascades have been implicated in mediating invasion in TRAIL-resistant forms of lung cancer [34]. Thus, a better understanding of TRAIL-controlled signaling pathways in human cancers is warranted to exploit the anticancer activity of this death receptor system for cancer therapy to the best possible extent. Furthermore, cFLIP can serve as a target for therapeutic intervention in human cancers. To this end, a variety of strategies have been developed to interfere with cFLIP expression or its function in cancers. Since cFLIP exhibits a short protein half-life and a high protein turnover rate, one possibility is to interfere with its transcription or translation via pharmacological compounds. For example, mTOR inhibitors have been shown to suppress cFLIP protein expression by blocking its translation [35]. In addition, histone deacetylase (HDAC) inhibitors have been described to downregulate cFLIP protein expression in a number of human cancers [36–38]. This has been attributed to the ability of HDAC inhibitors to upregulated c-Myc, a transcription factor that negatively regulates cFLIP transcription [37]. Also, HDAC inhibitors have been reported to cause increased acetylation of KU70 which in turn releases cFLIP from its interaction with KU70 and promotes its degradation via the proteasome [38]. Moreover, a number of approaches were designed to stimulate re-expression of caspase-8 in cancers with epigenetic silencing of caspase-8. This includes the use of demethylating agents such as 5aza-2 -deoxycytidine which were shown to cause demethylation of the regulatory sequence of caspase-8, leading to transcriptional activation and re-expression of caspase-8, thereby sensitizing cancer cells to apoptosis [17,18,39]. Since caspase-8 also contains interferon-sensitive response elements in its promoter region, type 1 and type 2 interferons such as interferon-␥ have been exploited to stimulate caspase-8 expression, resulting in increased apoptosis in response to death receptor ligands, chemo- or radiotherapy [40,41]. In addition, retinoic acid has been described to transcriptionally activate caspase-8 via a cyclic AMP-responsive element-binding protein (CREB)-binding domain, which was associated with increased cell death in response to chemotherapeutics or TNF␣ [42].

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6. Conclusions

Signaling via the mitochondrial (intrinsic) pathway of apoptosis is frequently impaired in human cancers. Since mitochondrial outer membrane permeabilization is tightly controlled by various factors including the Bcl-2 family of pro- and antiapoptotic proteins, genetic alterations or posttranslational modifications of Bcl-2 proteins can confer cell death resistance in human cancers. In follicular lymphoma, chromosomal translocation of the Bcl-2 oncogene into the immunoglobulin heavy chain gene locus results in aberrant transcriptional activation of Bcl-2 and high expression levels [43]. Also, genetic alterations in the proapoptotic Bcl-2 family

The concept to rationally target apoptosis signal transduction pathways has important implication for cancer therapy, since intact apoptosis programs are critical for the therapeutic efficacy of most anticancer therapies. Reactivation of apoptosis not only directly triggers cell death in cancer cells, but also lowers the threshold for apoptosis in response to other apoptotic stimuli, thus sensitizing tumor cells for apoptosis. In principle, the idea to target apoptosis pathways has been translated into first clinical applications. The challenge in future years will be to further exploit this concept for cancer therapy to the best extent as possible.

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Conflict of interest statement The author declares that there are no conflicts of interest.

Acknowledgements

The expert secretarial assistance of C. Hugenberg is greatly 307 appreciated. This work has been partially supported by grants from 308 Q3 the Deutsche Forschungsgemeinschaft, the Ministerium für Bil309 dung und Forschung (01GM1104C), IUAP, LOEWE, Deutsche Kreb310 shilfe, Wilhelm-Sander-Stiftung, Else-Kröner Fresenius-Stiftung 311 and Jose-Carreras Stiftung. 306

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References [1] Lockshin RA, Zakeri Z. Cell death in health and disease. J Cell Mol Med 2007;11:1214–24. [2] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. [3] Fulda S. Tumor resistance to apoptosis. Int J Cancer 2009;124:511–5. [4] Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 2006;25:4798–811. [5] Ashkenazi A. Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev 2008;19:325–31. [6] Fulda S, Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 2012;11:109–24. [7] Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441–6. [8] Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001;412:95–9. [9] Friesen C, Fulda S, Debatin KM. Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells. Leukemia 1997;11:1833–41. [10] Jin Z, McDonald III ER, Dicker DT, El-Deiry WS. Deficient tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) death receptor transport to the cell surface in human colon cancer cells selected for resistance to TRAIL-induced apoptosis. J Biol Chem 2004;279:35829–39. [11] Pai SI, Wu GS, Ozoren N, Wu L, Jen J, Sidransky D, et al. Rare loss-of-function mutation of a death receptor gene in head and neck cancer. Cancer Res 1998;58:3513–8. [12] Dechant MJ, Fellenberg J, Scheuerpflug CG, Ewerbeck V, Debatin KM. Mutation analysis of the apoptotic “death-receptors” and the adaptors TRADD and FADD/MORT-1 in osteosarcoma tumor samples and osteosarcoma cell lines. Int J Cancer 2004;109:661–7. [13] Beltinger C, Kurz E, Bohler T, Schrappe M, Ludwig WD, Debatin KM. CD95 (APO1/Fas) mutations in childhood T-lineage acute lymphoblastic leukemia. Blood 1998;91:3943–51. [14] Beltinger C, Bohler T, Karawajew L, Ludwig WD, Schrappe M, Debatin KM. Mutation analysis of CD95 (APO-1/Fas) in childhood B-lineage acute lymphoblastic leukaemia. Br J Haematol 1998;102:722–8. [15] Sheikh MS, Huang Y, Fernandez-Salas EA, El-Deiry WS, Friess H, Amundson S, et al. The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene 1999;18:4153–9. [16] Fulda S. Caspase-8 in cancer biology and therapy. Cancer Lett 2009;281:128–33. [17] Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 2000;6:529–35. [18] Fulda S, Kufer MU, Meyer E, van Valen F, Dockhorn-Dworniczak B, Debatin KM. Sensitization for death receptor- or drug-induced apoptosis by reexpression of caspase-8 through demethylation or gene transfer. Oncogene 2001;20:5865–77. [19] Harada K, Toyooka S, Shivapurkar N, Maitra A, Reddy JL, Matta H, et al. Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res 2002;62:5897–901. [20] Hopkins-Donaldson S, Ziegler A, Kurtz S, Bigosch C, Kandioler D, Ludwig C, et al. Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ 2003;10:356–64. [21] Grotzer MA, Eggert A, Zuzak TJ, Janss AJ, Marwaha S, Wiewrodt BR, et al. Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 2000;19:4604–10. [22] Fulda S. Targeting c-FLICE-like inhibitory protein (CFLAR) in cancer. Expert Opin Ther Targets 2013;17:195–201. [23] Fulda S, Meyer E, Debatin KM. Metabolic inhibitors sensitize for CD95 (APO1/Fas)-induced apoptosis by down-regulating Fas-associated death domainlike interleukin 1-converting enzyme inhibitory protein expression. Cancer Res 2000;60:3947–56.

[24] Longley DB, Wilson TR, McEwan M, Allen WL, McDermott U, Galligan L, et al. c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene 2006;25:838–48. [25] Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer 2009;9:361–71. [26] Chow LQ, Eckhardt SG, Gustafson DL, O’Bryant C, Hariharan S, Diab S, et al. HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase 1 and PK study. J Clin Oncol 2006;24:2515. [27] Herbst RS, Mendolson DS, Ebbinghaus S, Gordon MS, O’Dwyer P, Lieberman G, et al. A phase I safety and pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-inducing protein in patients with advanced cancer. J Clin Oncol 2006;24:3013. [28] Patnaik A, Wakelee H, Mita M, Fitzgerald A, Hill M, Fox N, et al. HGS-ETR2 – a fully human monoclonal antibody to TRAIL-R2: results of a phase I trial in patients with advanced solid tumors. In: Proceedings Am Soc Clin Oncol 42nd Annual Meeting. 2006. p. A3012. [29] Tolcher AW, Mita M, Meropol NJ, von Mehren M, Patnaik A, Padavic K, et al. Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol 2007;25:1390–5. [30] Takimoto R, El-Deiry WS. Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene 2000;19:1735–43. [31] Meng RD, El-Deiry WS. p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. Exp Cell Res 2001;262:154–69. [32] Lacour S, Micheau O, Hammann A, Drouineaud V, Tschopp J, Solary E, et al. Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells. Oncogene 2003;22:1807–16. [33] Ehrhardt H, Fulda S, Schmid I, Hiscott J, Debatin KM, Jeremias I. TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB. Oncogene 2003;22:3842–52. [34] Azijli K, Yuvaraj S, Peppelenbosch MP, Wurdinger T, Dekker H, Joore J, et al. Kinome profiling of non-canonical TRAIL signaling reveals RIP1-Src-STAT3dependent invasion in resistant non-small cell lung cancer cells. J Cell Sci 2012;125:4651–61. [35] Panner A, James CD, Berger MS. Pieper RO. mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol Cell Biol 2005;25:8809–23. [36] Pathil A, Armeanu S, Venturelli S, Mascagni P, Weiss TS, Gregor M, et al. HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology 2006;43: 425–34. [37] Bangert A, Cristofanon S, Eckhardt I, Abhari BA, Kolodziej S, Hacker S, et al. Histone deacetylase inhibitors sensitize glioblastoma cells to TRAILinduced apoptosis by c-myc-mediated downregulation of cFLIP. Oncogene 2012;31:4677–88. [38] Kerr E, Holohan C, McLaughlin KM, Majkut J, Dolan S, Redmond K, et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ 2012;19:1317–27. [39] Hopkins-Donaldson S, Bodmer JL, Bourloud KB, Brognara CB, Tschopp J, Gross N. Loss of caspase-8 expression in highly malignant human neuroblastoma cells correlates with resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 2000;60:4315–9. [40] Casciano I, De Ambrosis A, Croce M, Pagnan G, Di Vinci A, Allemanni G, et al. Expression of the caspase-8 gene in neuroblastoma cells is regulated through an essential interferon-sensitive response element (ISRE). Cell Death Differ 2004;11:131–4. [41] Fulda S, Debatin KM. IFNgamma sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway. Oncogene 2002;21:2295–308. [42] Jiang M, Zhu K, Grenet J, Lahti JM. Retinoic acid induces caspase-8 transcription via phospho-CREB and increases apoptotic responses to death stimuli in neuroblastoma cells. Biochim Biophys Acta 2008;1783:1055–67. [43] Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 1984;226:1097–9. [44] Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997;275:967–9. [45] Kitada S, Pedersen IM, Schimmer AD, Reed JC. Dysregulation of apoptosis genes in hematopoietic malignancies. Oncogene 2002;21:3459–74. [46] Tagawa H, Karnan S, Suzuki R, Matsuo K, Zhang X, Ota A, et al. Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 2005;24:1348–58. [47] Tan TT, Degenhardt K, Nelson DA, Beaudoin B, Nieves-Neira W, Bouillet P, et al. Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 2005;7:227–38. [48] Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435:677–81. [49] Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006;10:375–88.

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[50] van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006;10:389–99. [51] Chen S, Dai Y, Harada H, Dent P, Grant S. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res 2007;67:782–91. [52] Yecies D, Carlson NE, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 2010;115:3304–13. [53] Tromp JM, Geest CR, Breij EC, Elias JA, van Laar J, Luijks DM, et al. Tipping the Noxa/Mcl-1 balance overcomes ABT-737 resistance in chronic lymphocytic leukemia. Clin Cancer Res 2012;18:487–98. [54] Lin X, Morgan-Lappe S, Huang X, Li L, Zakula DM, Vernetti LA, et al. ‘Seed’ analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene 2007;26:3972–9. [55] Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 2007;104:19512–7. [56] Miller LA, Goldstein NB, Johannes WU, Walton CH, Fujita M, Norris DA, et al. BH3 mimetic ABT-737 and a proteasome inhibitor synergistically kill melanomas through Noxa-dependent apoptosis. J Invest Dermatol 2009;129:964–71. [57] Hikita H, Takehara T, Shimizu S, Kodama T, Shigekawa M, Iwase K, et al. The BclxL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Hepatology 2010;52:1310–21.

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[58] Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013;19:202–8. [59] Vandenberg CJ, Cory S. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood 2013;121:2285–8. [60] Vaillant F, Merino D, Lee L, Breslin K, Pal B, Ritchie ME, et al. Targeting BCL2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 2013;24:120–9. [61] Touzeau C, Dousset C, Le Gouill S, Sampath D, Leverson JD, Souers AJ, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia 2014;28:210–2. [62] Vogler M, Dinsdale D, Dyer MJ, Cohen GM. ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets. Br J Haematol 2013;163:139–42. [63] Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov 2014;4:362–75. [64] Bogenberger JM, Delman D, Hansen N, Valdez R, Fauble V, Mesa RA, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-Azacytidine in myeloid malignancies. Leuk Lymphoma 2014 [Epub ahead of print].

Please cite this article in press as: Fulda S. Targeting apoptosis for anticancer therapy. Semin Cancer Biol (2014), http://dx.doi.org/10.1016/j.semcancer.2014.05.002

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Targeting apoptosis for anticancer therapy.

Programmed cell death via apoptosis is characteristically disturbed in human cancers. This facilitates not only tumor formation and progression, but a...
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