title: Induction of apoptosis and suppression of angiogenesis of hepatocellular carcinoma by HS-159, a novel phosphatidylinositol 3-kinase inhibitor.
abstract: The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer and is emerging as an attractive therapeutic target. In this study, we synthesized a novel PI3Kα inhibitor, HS-159 [N-(5-(3-(3-cyanophenyl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide] and evaluated its anticancer effects on Huh-7 human hepatocellular carcinoma (HCC) cells. HS-159 effectively inhibited the phosphorylation of downstream PI3K effectors such as Akt, mTOR and P70S6 kinases in a dose-dependent manner. This compound also induced apoptosis and increased the fraction of apoptotic cells in the sub-G1 phase as well as the levels of cleaved PARP, caspase-3 and -9. Furthermore, HS-159 decreased the expression of hypoxia inducible factor-1α and vascular endothelial growth factor which play important roles in angiogenesis. The anti-angiogenic effect of HS-159 was confirmed by the suppression of tube formation and migration of human umbilical vein endothelial cells in vitro. Collectively, our results demonstrate that HS-159 exhibited anticancer activities including the induction of apoptosis and inhibition of angiogenesis by blocking the PI3K/Akt pathway in Huh-7 cells. Therefore, we suggest that this drug may be potentially used for targeted HCC therapy.
authors.affiliation: College of Medicine, Inha University, Jung-gu, Incheon 400-712, Republic of Korea.
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Yun
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Jung
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; C585463:N-(5-(3-(3-cyanophenyl)imidazo(1,2-a)pyridin-6-yl)pyridin-3-yl)benzenesulfonamide; D000096926:Benzenesulfonamides