Apigenin blocks IKKα activation and suppresses prostate cancer progression

Abstract

IKKα has been implicated as a key regulator of oncogenesis and driver of the metastatic process; therefore is regarded as a promising therapeutic target in anticancer drug development. In spite of the progress made in the development of IKK inhibitors, no potent IKKα inhibitor(s) have been identified. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone apigenin as a specific IKKα inhibitor. Here we report apigenin, in micro molar range, inhibits IKKα kinase activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays and exhibits anticancer efficacy in experimental tumor model. We found that apigenin directly binds with IKKα, attenuates IKKα kinase activity and suppresses NF-ĸB/p65 activation in human prostate cancer PC-3 and 22Rv1 cells much more effectively than IKK inhibitor, PS1145. We also showed that apigenin caused cell cycle arrest similar to knockdown of IKKα in prostate cancer cells. Studies in xenograft mouse model indicate that apigenin feeding suppresses tumor growth, lowers proliferation and enhances apoptosis. These effects correlated with inhibition of p-IKKα, NF-ĸB/p65, proliferating cell nuclear antigen and increase in cleaved caspase 3 expression in a dose-dependent manner. Overall, our results suggest that inhibition of cell proliferation, invasiveness and decrease in tumor growth by apigenin are mediated by its ability to suppress IKKα and downstream targets affecting NF-ĸB signaling pathways.

Role of Apigenin in Cancer Prevention via the Induction of Apoptosis and Autophagy

“…The oral administration of apigenin (20 and 50 μg/mice) decreased the volume and wet weight of tumors in nude mice bearing human prostate cancer, without any undesirable side effects 27–30. Apigenin intake also decreased serum-IGF-I level and induced apoptosis and cell cycle arrest in tumor xenograft.…”

“…Apigenin intake also decreased serum-IGF-I level and induced apoptosis and cell cycle arrest in tumor xenograft. 27,29,31,32 Apigenin was shown to interrupt the NF-κB signaling pathways; this was responsible for the suppression of prostate cancer progression 30. Moreover, apigenin significantly decreased the level of Her2/neu, a protein involved in growth factor signaling, which indicated a reduction in breast cancer cell proliferation in apigenin-treated mice 33.…”

Plant Flavone Apigenin: an Emerging Anticancer Agent

“…Additional evidence supported that apigenin-mediated reduction in cell proliferation, invasiveness, and decrease in tumor growth results from the downregulation of IKKα and downstream targets affecting NF-κB signaling pathways [126]. Shukla et al [127] elucidated that apigenin directly binds to IKKα, inhibiting its kinase activity. Apigenin treatment restored IκBα expression, preventing its phosphorylation by upstream kinase IKK which undergoes proteasomal degradation [127].…”

“…Shukla et al [127] elucidated that apigenin directly binds to IKKα, inhibiting its kinase activity. Apigenin treatment restored IκBα expression, preventing its phosphorylation by upstream kinase IKK which undergoes proteasomal degradation [127]. Further assessment by Shukla et al [128] examined the apigenin-induced 22Rv1 tumor growth inhibition subcutaneously implanted in athymic male nude mice.…”

Inflammatory related gene IKKα, IKKβ, IKKγ cooperates to determine liver cancer stem cells progression by altering telomere via heterochromatin protein 1-HOTAIR axis

“…Many diseases are related to IKK [1]. IKKα has been implicated as a key regulator of oncogenesis by affecting NF-ĸB signaling pathways [2]. Activation of IKK-β contributes to cancer pathogenesis and inflammatory disease [3].…”