Considering the role of
retinoids in regulation of more than 500 genes involved in cell cycle and growth arrest, a detailed understanding of the mechanism and its regulation is useful for
therapy. The extract of the medicinal plant Neem (Azadirachta indica) is used against several ailments especially for anti-inflammatory, anti-
itching, spermicidal, anticancer, and insecticidal activities. In this report we prove the detailed mechanism on the regulation of
retinoic acid-mediated cell signaling by
azadirachtin, active components of neem extract.
Azadirachtin repressed
all trans-retinoic acid (ATRA)-mediated nuclear
transcription factor κB (NF-κB) activation, not the
DNA binding but the NF-κB-dependent gene expression. It did not inhibit IκBα degradation, IκBα
kinase activity, or p65 phosphorylation and its nuclear translocation but inhibited NF-κB-dependent reporter gene expression.
Azadirachtin inhibited TRAF6-mediated, but not TRAF2-mediated NF-κB activation. It inhibited ATRA-induced Sp1 and CREB (
cAMP-response element-binding protein)
DNA binding.
Azadirachtin inhibited ATRA binding with
retinoid receptors, which is supported by biochemical and in silico evidences.
Azadirachtin showed strong interaction with
retinoid receptors. It suppressed ATRA-mediated removal of
retinoid receptors, bound with
DNA by inhibiting ATRA binding to its receptors. Overall, our data suggest that
azadirachtin interacts with
retinoic acid receptors and suppresses ATRA binding, inhibits falling off the receptors, and activates
transcription factors like CREB, Sp1, NF-κB, etc. Thus,
azadirachtin exerts anti-inflammatory and anti-metastatic responses by a novel pathway that would be beneficial for further anti-inflammatory and anti-
cancer therapies.