Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1,1-bis(3'-indoly)-1-(p-substituted phenyl)methanes.
1,1-Bis(3'-indoly)-1-(p-substituted phenyl)methanes (C-DIM) exhibit structure-dependent activation of peroxisome proliferator-activated receptor gamma and nerve growth factor-induced Balpha (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 gamma 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 NH(2) 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.
Lei
Ping
P
Institute of Biosciences and Technology, Texas A&M University, College Station, Texas 77843-4466, USA.
Abdelrahim
Maen
M
Cho
Sung Dae
SD
Liu
Xinyi
X
Liu
Xingi
X
Safe
Stephen
S
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004721:Endoplasmic Reticulum / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047495:PPAR gamma / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D011987:Receptors, Steroid / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007211:Indoles; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047495:PPAR gamma; D011987:Receptors, Steroid; C030374:indole; D048031:JNK Mitogen-Activated Protein Kinases