title: A novel imidazopyridine derivative, HS-106, induces apoptosis of breast cancer cells and represses angiogenesis by targeting the PI3K/mTOR pathway.
abstract: Abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is an essential step for the formation and growth of tumors in humans. HS-106 is an imidazopyridine derivative that inhibits the kinase activity of PI3K by binding to the ATP-binding cleft. We found that this compound suppressed breast cancer cell proliferation and induced apoptosis by specifically inhibiting the activity of target proteins in the PI3K/Akt/mTOR signaling pathway. Cell cycle analysis revealed that treatment with HS-106 resulted in cell cycle arrest at the G(2)/M phase due to up-regulation of p-cdc25 and down-regulation of cyclin B1. Also, HS-106 induced apoptosis by increasing the levels of cleaved caspase-3 and cleaved PARP. In addition, chromatin condensation and apoptotic bodies were detected in HS-106-treated breast cancer cells. Furthermore, HS-106 decreased the expression of hypoxia-inducible factor 1α (HIF-1α), and inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs) in vitro and blood vessel formation in an in vivo Matrigel plug assay. These results show that HS-106 may be an effective novel therapeutic candidate in clinical trials as a potential treatment for human breast cancers or other advanced malignancies with aberrant PI3K/Akt/mTOR signaling.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon, Republic of Korea
authors.forename: Guang-Yong
authors.initials: GY
authors.lastname: Li
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Jung
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.forename: Mi Kwon
authors.initials: MK
authors.lastname: Son
authors.forename: JuHyeon
authors.initials: J
authors.lastname: Seo
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Hong
authors.forename: Yujeong
authors.initials: Y
authors.lastname: Jeong
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015197:Carcinogenicity Tests; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D020533:Angiogenesis Inhibitors; D056744:Cyclin B1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C534699:CCNB1 protein, human; C497442:HIF1A protein, human; C580594:HS-106; D000096926:Benzenesulfonamides; C467484:VEGFA protein, human; C546842:MTOR protein, human