Small molecule XIAP inhibitors enhance TRAIL-Lnduced apoptosis and antitumor activity in preclinical models of pancreatic carcinoma

Tobias Longin Haas, Meike Vogler, Henning Walczak, Dominic Stadel, Felicitas Genze, Marjana Jovanovic, Umesh Bhanot, Cornelia Hasel, Peter Möller, Jürgen E. Gschwend, Thomas Simmet, Klaus-Michael Debatin, Simone Fulda

Research output: Contribution to journalArticle

130 Citations (Scopus)

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-Iinked 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 TRAIL-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. © 2009 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)2425-2434
Number of pages10
JournalCancer Research
Volume69
DOIs
Publication statusPublished - 2009

Keywords

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis
  • Cancer Research
  • Carcinoma, Pancreatic Ductal
  • Caspase 3
  • Drug Synergism
  • Enzyme Activation
  • Female
  • HCT116 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Mitochondria
  • Oncology
  • Pancreatic Neoplasms
  • TNF-Related Apoptosis-Inducing Ligand
  • X-Linked Inhibitor of Apoptosis Protein
  • Xenograft Model Antitumor Assays

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