Targeting XIAP for the treatment of malignancy

Schimmer, Aaron D.; Dalili, Shadi; Batey, Robert A.; Riedl, Stefan J.

doi:10.1038/sj.cdd.4401826

Cited by 276 publications

(252 citation statements)

References 72 publications

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“…However, elevated levels of IAPs are often associated with resistance to apoptosis in human cancer cells and lowering IAPs using SMAC mimetics is known to sensitise cells to cytotoxic agents. 140,141 Perspectives It has been around 15 years since the first caspase was discovered. During this time, the pendulum has shifted from earlier predictions that all caspases play some role in the execution of apoptosis, to caspases may not be required for many forms cell deaths.…”

Section: Regulators Of Mammalian Caspasesmentioning

confidence: 99%

Caspase function in programmed cell death

2006

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The first proapoptotic caspase, CED-3, was cloned from Caenorhabditis elegans in 1993 and shown to be essential for the developmental death of all somatic cells. Following the discovery of CED-3, caspases have been cloned from several vertebrate and invertebrate species. As reviewed in other articles in this issue of Cell Death and Differentiation, many caspases function in nonapoptotic pathways. However, as is clear from the worm studies, the evolutionarily conserved role of caspases is to execute programmed cell death. In this article, I will specifically focus on caspases that function primarily in cell death execution. In particular, the physiological function of caspases in apoptosis is discussed using examples from the worm, fly and mammals.

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Section: Regulators Of Mammalian Caspasesmentioning

confidence: 99%

Caspase function in programmed cell death

2006

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“…Further, studies have revealed that of the three BIR domains of XIAP, BIR-2 inhibits the downstream caspase-3 and caspase-7, whereas BIR-3 inhibits the upstream caspase-9 (19 -21). In light of its frequent overexpression in human cancers and its known function as a roadblock to apoptosis, XIAP also represents a candidate therapeutic target in cancer cells (22).…”

Section: Introductionmentioning

confidence: 99%

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

Karikari¹,

Roy²,

Tryggestad

et al. 2007

Molecular Cancer Therapeutics

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Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists (''XAntag''; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC 50 in the range of 2 to 5 Mmol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream ''effector'' caspases (caspase-3 and caspase-7) versus the upstream ''initiator'' caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation. [Mol Cancer Ther 2007;6(3):957 -66]

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“…The eight known members of the human IAP family are characterized by at least one baculoviral IAP repeat (BIR), a domain known to bind caspases, the proteases responsible for apoptosis. Several IAPs also contain an E2-binding RING finger domain at the carboxy terminus imparting E3 ligase activity, which mediates both autoubiquitination and ubiquitination of various substrates (Salvesen and Duckett, 2002;Eckelman et al, 2006;Schimmer et al, 2006). Cellular IAP1 and IAP2 were first identified by their association with TNFa-receptorassociated factors À1 and À2 (TRAFs), adapter proteins that associate with various members of the tumor necrosis factor (TNF) receptor family and that mediate activation of protein kinases involved in NF-kB induction and other signal transduction events (Rothe et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

TRAF2-binding BIR1 domain of c-IAP2/MALT1 fusion protein is essential for activation of NF-κB

2009

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Marginal zone mucosa-associated lymphoid tissue (MALT) B-cell lymphoma is the most common extranodal non-Hodgkin lymphoma. The t(11;18)(q21;q21) translocation occurs frequently in MALT lymphomas and creates a chimeric NF-jB-activating protein containing the baculoviral IAP repeat (BIR) domains of c-IAP2 (inhibitor of apoptosis protein 2) fused with portions of the MALT1 protein. The BIR1 domain of c-IAP2 interacts directly with TRAF2 (TNFa-receptor-associated factor-2), but its role in NF-jB activation is still unclear. Here, we investigated the role of TRAF2 in c-IAP2/MALT1-induced NF-jB activation. We show the BIR1 domain of c-IAP2 is essential for NF-jB activation, whereas BIR2 and BIR3 domains are not. Studies of c-IAP2/MALT1 BIR1 mutant (E47A/R48A) that fails to activate NF-jB showed loss of TRAF2 binding, but retention of TRAF6 binding, suggesting that interaction of c-IAP2/MALT1 with TRAF6 is insufficient for NF-jB induction. In addition, a dominant-negative TRAF2 mutant or downregulation of TRAF2 achieved by small interfering RNA inhibited NF-jB activation by c-IAP2/MALT1 showing that TRAF2 is indispensable. Comparisons of the bioactivity of intact c-IAP2/MALT1 oncoprotein and BIR1 E47A/R48A c-IAP2/MALT1 mutant that cannot bind TRAF2 in a lymphoid cell line provided evidence that TRAF2 interaction is critical for c-IAP2/MALT1-mediated increases in the NF-jB activity, increased expression of endogenous NF-jB target genes (c-FLIP, TRAF1), and resistance to apoptosis.

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Targeting XIAP for the treatment of malignancy

Cited by 276 publications

References 72 publications

Caspase function in programmed cell death

Caspase function in programmed cell death

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

TRAF2-binding BIR1 domain of c-IAP2/MALT1 fusion protein is essential for activation of NF-κB

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