title: TCH1036, a indeno[1,2-c]quinoline derivative, potentially inhibited the growth of human brain malignant glioma (GBM) 8401 cells via suppression of the expression of Suv39h1 and PARP.
abstract: A newly synthesized Indeno[1,2-c]quinoline derivative, which has previously been found to potentially trap DNA-topoisomerase cleavage complexes more effectively than camptothecin, could effectively inhibit the proliferation of a variety of cancers, such as breast cancer treated with TCH1030. In this study, we further explore the activity of the TCH1036, TCH1259 and TCH1030 compounds in suppressing the growth of human brain malignant glioma (GBM) 8401 cells, in addition to elucidating the related mechanisms. According to tests of cytotoxicity, the GBM cells were more sensitive to the inhibitory effects of the TCH1036 compound than to those of the other two compounds. Moreover, the accumulation of GBM cells in the sub-G1 and G2/M phases was clearly induced by the TCH1036 compound in a dose-dependent manner. A screening of the majority of histone-modifier enzymes indicated that the expression of Suv39h1 in the GBM cells was attenuated by treatment with each of the TCH compounds, an observation which was further confirmed by Western blotting. The increase in active-form caspase 3 in the GBM cells treated with TCH compounds caused a high degree of poly (ADP-ribose) polymerase (PARP) cleavage and also enhanced the high ratio of hypodiploid GBM cells in the sub-G1 phase. In molecular docking simulations, it was observed that the stable forms of the TCH compounds could successfully insert into the catalytic pocket of PARP, with the highest affinity being between PARP and the TCH1036 compound. These findings suggested that the TCH1036 compound would be a promising compound in the treatment of brain malignant glioma.
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 40402, Taiwan; School of Medicine, China Medical University, Taichung 40402, Taiwan.
authors.forename: Hsien-Feng
authors.initials: HF
authors.lastname: Liao
authors.affiliation: Epigenome Research Center, China Medical University Hospital, Taichung 40402, Taiwan.
authors.forename: Chien-Chin
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Graduate Institute of applied Chemistry, National Chiayi University, Chiayi 60004, Taiwan.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Hsiao
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 40402, Taiwan; School of Medicine, China Medical University, Taichung 40402, Taiwan.
authors.forename: Yi-Fong
authors.initials: YF
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80761, Taiwan.
authors.forename: Chih-Hua
authors.initials: CH
authors.lastname: Tseng
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80761, Taiwan.
authors.forename: Cherng-Chyi
authors.initials: CC
authors.lastname: Tzeng
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80761, Taiwan.
authors.forename: Yeh-Long
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Graduate Institute of applied Chemistry, National Chiayi University, Chiayi 60004, Taiwan.
authors.forename: Jui-Chang
authors.initials: JC
authors.lastname: Chen
authors.affiliation: Epigenome Research Center, China Medical University Hospital, Taichung 40402, Taiwan; Department of Laboratory Medicine, China Medical University Hospital, Taichung 40402, Taiwan. Electronic address: t25074@mail.cmuh.org.tw.
authors.forename: Ya-Sian
authors.initials: YS
authors.lastname: Chang
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 40402, Taiwan; School of Medicine, China Medical University, Taichung 40402, Taiwan; Epigenome Research Center, China Medical University Hospital, Taichung 40402, Taiwan; Department of Laboratory Medicine, China Medical University Hospital, Taichung 40402, Taiwan. Electronic address: d6781@mail.cmuh.org.tw.
authors.forename: Jan-Gowth
authors.initials: JG
authors.lastname: Chang
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D020134:Catalytic Domain; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D062105:Molecular Docking Simulation; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C583438:9-methoxy-6-(piperazin-1-yl)-11H-indeno(1,2-c)quinoline-11-one O-3-(dimethylamino)propyl oxime; D010091:Oximes; D011804:Quinolines; D012333:RNA, Messenger; D012097:Repressor Proteins; C037219:quinoline; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: GBM; HKMTs; PARP; Suv39h1; TCH1036