title: A synthetic naringenin derivative, 5-hydroxy-7,4'-diacetyloxyflavanone-N-phenyl hydrazone (N101-43), induces apoptosis through up-regulation of Fas/FasL expression and inhibition of PI3K/Akt signaling pathways in non-small-cell lung cancer cells.
abstract: Naringenin, a well-known naturally occurring flavonone, demonstrates cytotoxicity in a variety of human cancer cell lines; its inhibitory effects on tumor growth have spurred interest in its therapeutic application. In this study, naringenin was derivatized to produce more effective small-molecule inhibitors of cancer cell proliferation, and the anticancer effects of its derivative, 5-hydroxy-7,4'-diacetyloxyflavanone-N-phenyl hydrazone (N101-43), in non-small-cell lung cancer (NSCLC) cell lines NCI-H460, A549, and NCI-H1299 were investigated. Naringenin itself possesses no cytotoxicity against lung cancer cells. In contrast, N101-43 inhibits proliferation of both NCI-H460 and A549 cell lines; this capacity is lost in p53-lacking NCI-H1299 cells. N101-43 induces apoptosis via sub-G1 cell-cycle arrest in NCI-H460 and via G0/G1 arrest in A549 cells. Expression of apoptosis and cell-cycle regulatory factors is altered: Cyclins A and D1 and phospho-pRb are down-regulated, but expression of CDK inhibitors such as p21, p27, and p53 is enhanced by N101-43 treatment; N101-43 also increases expression levels of the extrinsic death receptor Fas and its binding partner FasL. Furthermore, N101-43 treatment diminishes levels of cell survival factors such as PI3K and p-Akt dose-dependently, and N101-43 additionally induces cleavage of the pro-apoptotic factors caspase-3, caspase-8, and poly ADP-ribose polymerase (PARP). Cumulatively, these investigations show that the naringenin derivative N101-43 induces apoptosis via up-regulation of Fas/FasL expression, activation of caspase cascades, and inhibition of PI3K/Akt survival signaling pathways in NCI-H460 and A549 cells. In conclusion, these data indicate that N101-43 may have potential as an anticancer agent in NSCLC.
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea.
authors.forename: Yesol
authors.initials: Y
authors.lastname: Bak
authors.forename: Heejong
authors.initials: H
authors.lastname: Kim
authors.forename: Jeong-Woo
authors.initials: JW
authors.lastname: Kang
authors.forename: Dong Hun
authors.initials: DH
authors.lastname: Lee
authors.forename: Man Sub
authors.initials: MS
authors.lastname: Kim
authors.forename: Yun Sun
authors.initials: YS
authors.lastname: Park
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Kang-Yeoun
authors.initials: KY
authors.lastname: Jung
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.forename: Jintae
authors.initials: J
authors.lastname: Hong
authors.forename: Do-Young
authors.initials: DY
authors.lastname: Yoon
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000235:genetics; D044950:Flavanones / Q000494:pharmacology*; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000235:genetics
chemical_list: C569245:5-hydroxy-7,4'-diacetyloxyflavanone-N-phenyl hydrazone; D053222:Fas Ligand Protein; D044950:Flavanones; D006835:Hydrazones; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019014:fas Receptor; D051057:Proto-Oncogene Proteins c-akt; C005273:naringenin