title: Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway.
abstract: Cudraflavone C (Cud C) is a naturally-occurring flavonol with reported anti-proliferative activities. However, the mechanisms by which Cud C induced cytotoxicity have yet to be fully elucidated. Here, we investigated the effects of Cud C on cell proliferation, caspase activation andapoptosis induction in colorectal cancer cells (CRC). We show that Cud C inhibits cell proliferation in KM12, Caco-2, HT29, HCC2998, HCT116 and SW48 CRC but not in the non-transformed colorectal epithelial cells, CCD CoN 841. Cud C induces tumor-selective apoptosis via mitochondrial depolarization and activation of the intrinsic caspase pathway. Gene expression profiling by microarray analyses revealed that tumor suppressor genes EGR1, HUWE1 and SMG1 were significantly up-regulated while oncogenes such as MYB1, CCNB1 and GPX2 were down-regulated following treatment with Cud C. Further analyses using Connectivity Map revealed that Cud C induced a gene signature highly similar to that of protein synthesis inhibitors and phosphoinositide 3-kinase (PI3K)-AKT inhibitors, suggesting that Cud C might inhibit PI3K-AKT signaling. A luminescent cell free PI3K lipid kinase assay revealed that Cud C significantly inhibited p110β/p85α PI3K activity, followed by p120γ, p110δ/p85α, and p110α/p85α PI3K activities. The inhibition by Cud C on p110β/p85α PI3K activity was comparable to LY-294002, a known PI3K inhibitor. Cud C also inhibited phosphorylation of AKT independent of NFκB activity in CRC cells, while ectopic expression of myristoylated AKT completely abrogated the anti-proliferative effects, and apoptosis induced by Cud C in CRC. These findings demonstrate that Cud C induces tumor-selective cytotoxicity by targeting the PI3K-AKT pathway. These findings provide novel insights into the mechanism of action of Cud C, and indicate that Cud C further development of Cud C derivatives as potential therapeutic agents is warranted.
authors.affiliation: School of Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Hsien-Chuen
authors.initials: HC
authors.lastname: Soo
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Felicia Fei-Lei
authors.initials: FF
authors.lastname: Chung
authors.affiliation: School of Pharmacy, University of Nottingham Malaysia Campus, Jalan Broga, Semenyih, Selangor, Malaysia.
authors.forename: Kuan-Hon
authors.initials: KH
authors.lastname: Lim
authors.affiliation: School of Pharmacy, University of Nottingham Malaysia Campus, Jalan Broga, Semenyih, Selangor, Malaysia.
authors.forename: Veronica Alicia
authors.initials: VA
authors.lastname: Yap
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
authors.affiliation: School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Ling-Wei
authors.initials: LW
authors.lastname: Hii
authors.affiliation: School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Si-Hoey
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Sze-Jia
authors.initials: SJ
authors.lastname: See
authors.affiliation: School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Yuen-Fen
authors.initials: YF
authors.lastname: Tan
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.|School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Chee-Onn
authors.initials: CO
authors.lastname: Leong
authors.affiliation: School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Chun-Wai
authors.identifier: http://orcid.org/0000-0001-6532-184X
authors.initials: CW
authors.lastname: Mai
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D047309:Flavones / Q000494:pharmacology*; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047309:Flavones; C000595858:cudraflavone C; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt