Nuclear factor-kappaB (
NF-kappaB), 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-kappaB activation by inflammatory
cytokines,
mitogens, and
viral infection, via direct binding and modification of the beta subunit of the
IkappaB kinase complex (IKK). Herein, we describe the
NF-kappaB-dependent anticancer activity of natural and synthetic
cyclopentenone IKK inhibitors. We demonstrate that the natural
cyclopentenone 15-deoxy-Delta(12,14)prostaglandin J(2) (15d-PGJ(2)) is a potent inhibitor of constitutive
IkappaB-kinase and
NF-kappaB activities in
chemotherapy-resistant ER-negative
breast cancer cells. 15d-PGJ(2)-induced inhibition of
NF-kappaB function is rapidly followed by down-regulation of
NF-kappaB-dependent antiapoptotic
proteins cIAPs 1/2, Bcl-X(L), 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-kappaB 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-kappaB regulation.