RT Journal Article
SR Electronic
T1 Induction of Apoptosis in Estrogen Receptor-Negative Breast Cancer Cells by Natural and Synthetic Cyclopentenones: Role of the IκB Kinase/Nuclear Factor-κB Pathway
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1812
OP 1821
DO 10.1124/mol.106.025759
VO 70
IS 5
A1 Alessandra Ciucci
A1 Patrizia Gianferretti
A1 Roberto Piva
A1 Thierry Guyot
A1 Timothy J. Snape
A1 Stanley M. Roberts
A1 M. Gabriella Santoro
YR 2006
UL http://molpharm.aspetjournals.org/content/70/5/1812.abstract
AB Nuclear factor-κB (NF-κB), a transcription factor with a critical role in promoting inflammation and cell survival, is constitutively activated in estrogen-receptor (ER)-negative breast cancer and is considered a potential therapeutic target for this type of neoplasia. We have previously demonstrated that cyclopentenone prostaglandins are potent inhibitors of NF-κB activation by inflammatory cytokines, mitogens, and viral infection, via direct binding and modification of the β subunit of the IκB kinase complex (IKK). Herein, we describe the NF-κB-dependent anticancer activity of natural and synthetic cyclopentenone IKK inhibitors. We demonstrate that the natural cyclopentenone 15-deoxy-Δ12,14prostaglandin J2 (15d-PGJ2) is a potent inhibitor of constitutive IκB-kinase and NF-κB activities in chemotherapy-resistant ER-negative breast cancer cells. 15d-PGJ2-induced inhibition of NF-κB function is rapidly followed by down-regulation of NF-κB-dependent antiapoptotic proteins cIAPs 1/2, Bcl-XL, and cellular FLICE-inhibitory protein, leading to caspase activation and induction of apoptosis in breast cancer cells resistant to treatment with paclitaxel and doxorubicin. We then demonstrate that the cyclopentenone ring structure is responsible for these activities, and we identify a new synthetic cyclopentenone derivative, 3-tert-butyldimethylsilyloxy-5-(E)-iso-propylmethylenecyclopent-2-enone (CTC-35), as a potent NF-κB inhibitor with proapoptotic activity in ER-negative breast cancer cells. The results open new perspectives in the search for novel proapoptotic molecules effective in the treatment of cancers presenting aberrant NF-κB regulation. The American Society for Pharmacology and Experimental Therapeutics