1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways.
1,1-Bis(3'-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu) is a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, and treatment of SKOV3 ovarian cancer cells with this compound (5 micromol/L) inhibits cell proliferation, whereas up to 15 micromol/L rosiglitazone had no effect on cell growth. DIM-C-pPhtBu also inhibits G0-G1 to S phase cell cycle progression and this is linked, in part, to PPARgamma-dependent induction of the cyclin-dependent kinase inhibitor p21. DIM-C-pPhtBu induces PPARgamma-independent down-regulation of cyclin D1 and we therefore further investigated activation of receptor-independent pathways. DIM-C-pPhtBu also induced apoptosis in SKOV3 cells and this was related to induction of glucose-related protein 78, which is typically up-regulated as part of the unfolded protein response during endoplasmic reticulum (ER) stress. Activation of ER stress was also observed in other ovarian cancer cell lines treated with DIM-C-pPhtBu. In addition, DIM-C-pPhtBu induced CCAAT/enhancer binding protein homologous protein through both ER stress and c-jun NH2-terminal kinase-dependent pathways, and CCAAT/enhancer binding protein homologous protein activated death receptor 5 and the extrinsic pathway of apoptosis. These results show that DIM-C-pPhtBu inhibits growth and induces apoptosis in ovarian cancer cells through both PPARgamma-dependent and PPARgamma-independent pathways, and this complex mechanism of action will be advantageous for future clinical development of these compounds for treatment of ovarian cancer.
Lei
Ping
P
Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M University, College Station, TX 77843-4466, USA.
Abdelrahim
Maen
M
Safe
Stephen
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D051742:Transcription Factor CHOP / Q000235:genetics; D054462:p21-Activated Kinases
C505816:1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane; C497249:DDIT3 protein, human; D007211:Indoles; D047495:PPAR gamma; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D019938:Cyclin D1; D051742:Transcription Factor CHOP; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D048031:JNK Mitogen-Activated Protein Kinases