title: HS-133, a novel fluorescent phosphatidylinositol 3-kinase inhibitor as a potential imaging and anticancer agent for targeted therapy.
abstract: As PI3K/Akt signaling is frequently deregulated in a wide variety of human tumors, PI3K inhibitors are an emerging class of drugs for cancer treatment. The monitoring of the drug behavior and distribution in the biological system can play an important role for targeted therapy and provide information regarding the response or resistance to available therapies. In this study, therefore, we have developed a family of xanthine derivatives, serving as a dual function exhibiting fluorescence, as well as inhibiting PI3K. Among them, HS-133 showed anti-proliferative effects and was monitored for its subcellular localization by a fluorescence microscopy. HS-133 suppressed the PI3K/Akt pathway and induced cell cycle arrest at the G0/G1 phase. The induction of apoptosis by HS-133 was confirmed by the increases of the cleaved PARP, caspase-3, and caspase-8. Furthermore, HS-133 decreased the protein expression of HIF-1α and VEGF, as well inhibited the tube formation and migration of the human umbilical vein endothelial cells. In vivo imaging also showed that tumors were visualized fluorescent with HS-133, and its oral administration significantly inhibited the growth of tumor in SkBr3 mouse xenograft models. Thus, we suggest that HS-133 may be used as a fluorescent anticancer agent against human breast cancer.
authors.affiliation: Department of Drug Development, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Drug Development, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Drug Development, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Drug Development, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Mi Kwon
authors.initials: MK
authors.lastname: Son
authors.affiliation: Department of Drug Development, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Yun
authors.affiliation: Drug Discovery Platform Technology Team, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Drug Discovery Platform Technology Team, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Kyeong-Ryoon
authors.initials: KR
authors.lastname: Lee
authors.affiliation: Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS) and Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS) and Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: Donghee
authors.initials: D
authors.lastname: Kim
authors.affiliation: Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS) and Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Drug Development, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005456:Fluorescent Dyes / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction; D014970:Xanthines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D014970:Xanthines