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Karikari CA, Roy I, Tryggestad E, Feldmann G, Pinilla C, Welsh K, Reed JC, Armour EP, Wong J, Herman J, Rakheja D, Maitra ATargeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein. Mol Cancer Ther 6: 957-966

Johns Hopkins University, Baltimore, Maryland, United States
Molecular Cancer Therapeutics (Impact Factor: 6.11). 04/2007; 6(3):957-66. DOI: 10.1158/1535-7163.MCT-06-0634
Source: PubMed

ABSTRACT 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 mumol/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.

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Available from: Clemencia Pinilla, May 19, 2014
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    • "However, the majority of apoptotic signaling is activated extracellularly via the binding of proapoptotic ligands from one cell to death receptors on the surface of another cell [6], [7]. For example, the ligands of the tumor necrosis factor (TNF) family bind to their receptors (e.g., TNF to TNFR, FasL to Fas, LIGHT to HVEM/TR2) and then trigger apoptotic signaling in response to unfavorable events [8], [9]. "
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    PLoS ONE 10/2013; 8(10):e74272. DOI:10.1371/journal.pone.0074272 · 3.23 Impact Factor
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    • "Drugs that target pro-survival or mitogenic kinases such as the EGF receptor inhibitor gefitinib and the multikinase inhibitor sorafenib sensitize resistant cancer cells to TRAIL through a variety of mechanisms involving downregulation of the anti-apoptotic proteins Mcl-1, c-FLIP and members of the IAP family (Kim et al 2008, Ricci et al 2007, Rosato et al 2007, Shrader et al 2007). Smac mimetics and XIAP inhibitors directly promote caspase-3 activity in resistant cell types (Bockbrader et al 2005, Karikari et al 2007). Finally, specific inhibition of Bcl-2 and Bcl-XL using the small molecule inhibitor ABT-737 (or its clinical version ABT-263) has shown promise in combination with TRAIL in certain contexts (Cristofanon and Fulda 2012, Hetschko et al 2007, Huang and Sinicrope 2008, Lickliter et al 2007, Song et al 2008). "
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    • "In pancreatic cancer, high expression levels of several of the IAP proteins have been reported in comparison to non-malignant pancreatic ductal cells or pancreatic tissue, including XIAP, cIAP2, survivin and livin [40-43]. In addition, low expression levels of XAF1 were recently shown to correlate with shorter survival times in pancreatic cancer [44]. "
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