Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1,1-bis(3′-indoly)-1-(p-substituted phenyl)methanes

Ping Lei, Maen Abdelrahim, Dae Cho Sung, Xingi Liu, Stephen Safe

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

1,1-Bis(3′-indoly)-1-(p-substituted phenyl)methanes (C-DIM) exhibit structure-dependent activation of peroxisome proliferator-activated receptor γ and nerve growth factor-induced Bα (Nur77) and induce receptor-dependent and receptor-independent apoptosis in cancer cells and tumors. In this study, we investigated the activation of apoptosis in pancreatic cancer cells by p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) and structurally related analogues that do not activate either peroxisome proliferator-activated receptor γ or Nur77. The ortho, meta, and para-bromo and -fluoro isomers all activated endoplasmic reticulum (ER) stress-dependent apoptosis in pancreatic cancer cells; however, methylation of the indole N group significantly decreased activity, suggesting that a free N was important for activation of ER stress. Both DIM-C-pPhBr and DIM-C-pPhF resembled the classic ER stress inducer thapsigargin in pancreatic cancer cells and activated ER stress markers, such as glucose-related protein 78 and the c-Jun NH2 kinase pathway, resulting in the induction of CCAAT/enhancer-binding protein homologous protein, death receptor 5, and the extrinsic apoptotic pathway. Moreover, DIM-C-pPhBr also inhibited tumor growth in an orthotopic model for pancreatic cancer, demonstrating the clinical potential for this C-DIM compound in pancreatic cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)3363-3372
Number of pages10
JournalMolecular Cancer Therapeutics
Volume7
Issue number10
DOIs
StatePublished - Oct 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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