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1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways

Lei, Ping ; Abdelrahim, Maen ; Safe, Stephen

Molecular cancer therapeutics, 2006-09, Vol.5 (9), p.2324-2336 [Periódico revisado por pares]

United States

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Título:
1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways
Autor: Lei, Ping ; Abdelrahim, Maen ; Safe, Stephen
Assuntos: Animals ; Apoptosis - drug effects ; Cell Cycle - drug effects ; Cell Growth Processes - drug effects ; Cyclin D1 - genetics ; Cyclin D1 - metabolism ; Down-Regulation - drug effects ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - metabolism ; Female ; Humans ; Indoles - pharmacology ; JNK Mitogen-Activated Protein Kinases - metabolism ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; p21-Activated Kinases ; PPAR gamma - agonists ; Protein-Serine-Threonine Kinases - biosynthesis ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Rabbits ; Receptors, TNF-Related Apoptosis-Inducing Ligand - immunology ; Transcription Factor CHOP - genetics
É parte de: Molecular cancer therapeutics, 2006-09, Vol.5 (9), p.2324-2336
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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.
Editor: United States
Idioma: Inglês

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1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways

Lei, Ping ; Abdelrahim, Maen ; Safe, Stephen

United States

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