Small Molecule XIAP Inhibitors Enhance TRAIL-Induced Apoptosis and Antitumor Activity in Preclinical Models of Pancreatic Carcinoma
- 15 March 2009
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (6), 2425-2434
- https://doi.org/10.1158/0008-5472.can-08-2436
Abstract
Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-linked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAM-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer. [Cancer Res 2009;69(6):2425-34]Keywords
Other Versions
This publication has 35 references indexed in Scilit:
- To kill a tumor cell: the potential of proapoptotic receptor agonistsJCI Insight, 2008
- Autocrine TNFα Signaling Renders Human Cancer Cells Susceptible to Smac-Mimetic-Induced ApoptosisCancer Cell, 2007
- Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis proteinMolecular Cancer Therapeutics, 2007
- Mitochondrial Membrane Permeabilization in Cell DeathPhysiological Reviews, 2007
- Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM)Blood, 2006
- Inhibition of clonogenic tumor growth: a novel function of Smac contributing to its antitumor activityOncogene, 2005
- A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell DeathScience, 2004
- TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-κBOncogene, 2003
- Targeting death and decoy receptors of the tumour-necrosis factor superfamilyNature Reviews Cancer, 2002
- IAP proteins: blocking the road to death's doorNature Reviews Molecular Cell Biology, 2002