Received for publication April 14, 2006.
Revised July 24, 2006.
Accepted for publication August 14, 2006.

Induction of Apoptosis in Estrogen-Receptor Negative Breast Cancer Cells by Natural and Synthetic Cyclopentenones: Role of the IKK/NF-B Pathway

Abstract

Nuclear factor-B (NF-B), 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-B activation by inflammatory cytokines, mitogens and viral infection, via direct binding and modification of the subunit of the IB kinase (IKK). Herein we describe the NF-B-dependent anticancer activity of natural and synthetic cyclopentenone IKK inhibitors. We demonstrate that the natural cyclopentenone 15-deoxy-^12,14prostaglandin J₂ (15d-PGJ₂) is a potent inhibitor of constitutive IB-kinase and NF-B activities in chemotherapy-resistant ER-negative breast cancer cells. 15d-PGJ₂-induced inhibition of NF-B function is rapidly followed by down-regulation of NF-B-dependent anti-apoptotic proteins cIAP1/2, Bcl-X_L and cFLIP, 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 identify a new synthetic cyclopentenone derivative, 3-tert-butyldimethylsilyloxy-5-(E)-iso-propylmethylenecyclopent-2-enone (CTC-35), as a potent NF-B inhibitor with pro-apoptotic activity in ER-negative breast cancer cells. The results open new perspectives in the search for novel pro-apoptotic molecules effective in the treatment of cancers presenting aberrant NF-B regulation.

Key words: Prostanoid, NFkappaB, Regulation - transcriptional, Apoptosis, Eicosanoids, Resistance, Transcription targets

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