title: 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.
authors.affiliation: Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.|The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.|The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Rajnee
authors.initials: R
authors.lastname: Kanwal
authors.affiliation: Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.|The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Eswar
authors.initials: E
authors.lastname: Shankar
authors.affiliation: Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Datt
authors.affiliation: Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Chance
authors.affiliation: Department of Epidemiology & Biostatistics, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.affiliation: Department of Pathology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: MacLennan
authors.affiliation: Department of Urology, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.|The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.|Department of Nutrition, Case Western Reserve University & University Hospitals Case Medical Center, Cleveland, Ohio 44106, USA.|Divison of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, USA.|Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays
chemical_list: D047310:Apigenin; D051550:I-kappa B Kinase
keywords: NF-ĸB signaling; apigenin; cell cycle; prostate cancer; therapeutic target