Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer

Cancer Res. 2010 Apr 1;70(7):2852-61. doi: 10.1158/0008-5472.CAN-09-3892. Epub 2010 Mar 23.

Abstract

Failure of chemotherapy in the treatment of pancreatic cancer is often due to resistance to therapy-induced apoptosis. A major mechanism for such resistance is the expression and activity of inhibitors of apoptosis proteins (IAP). Smac (second mitochondria-derived activator of caspase) is a mitochondrial protein that inhibits IAPs. We show that JP1201, a Smac mimetic, is a potent enhancer of chemotherapy in robust mouse models of pancreatic cancer. Combination of JP1201 with gemcitabine reduced primary and metastatic tumor burden in orthotopic xenograft and syngenic tumor models, induced regression of established tumors, and prolonged survival in xenograft and transgenic models of pancreatic cancer. The effect of JP1201 was phenocopied by XIAP small interfering RNA in vitro and correlated with elevated levels of tumor necrosis factor alpha protein in vivo. The continued development of JP1201 and other strategies designed to enhance therapy-induced apoptosis in pancreatic cancer is warranted.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis Regulatory Proteins
  • Biomimetic Materials / pharmacology*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Cell Line, Tumor
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Synergism
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, SCID
  • Mice, Transgenic
  • Mitochondrial Proteins / metabolism*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • TNF-Related Apoptosis-Inducing Ligand / administration & dosage
  • Tumor Necrosis Factor-alpha / biosynthesis
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors

Substances

  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • RNA, Small Interfering
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha
  • X-Linked Inhibitor of Apoptosis Protein
  • Deoxycytidine
  • gemcitabine