title: Apoptosis-inducing activity of trihaloacetylazulenes against human oral tumor cell lines.
abstract: Twenty-six trihaloacetylazulene derivatives were investigated for their tumor-specific cytotoxicity and apoptosis-inducing activity against three human normal cells (HGF, HPC, HPLF) and four human tumor cell lines (HSC-2, HSC-3, HSC-4, HL-60). The trichloroacetylazulenes [1b-13b] generally showed higher cytotoxicity as compared to the corresponding trifluoroacetylazulenes [1a-13a]. The trichloroacetylazulenes [1b-13b] also showed higher tumor-specific cytotoxicity (expressed as TS value) than the corresponding trifluoroacetylazulenes [1a-13a]. Especially, 2,3-dimethyl-1-trichloroacetylazulene [5b] and 1,3-ditrichloroacetyl-4,6,8-trimethylazulene [11b] showed the highest cytotoxicity and tumor specificity (TS > 35.6 and > 44.1, respectively). These compounds induced internucleosomal DNA fragmentation in HL-60 cells, but not in HSC-2 and HSC-3 cells, but activated caspase-3, -8 and -9 in all of these cells, suggesting the activation of both mitochondria-independent (extrinsic) and dependent (intrinsic) pathways. Western blot analysis showed that two compounds [5b, 11b] slightly increased the intracellular concentration of pro-apoptotic proteins (Bad, Bax) in HSC-2 cells. None of the 26 compounds showed anti-HIV activity. These results suggest [5b] and [11b] as possible candidates for future cancer chemotherapy.
authors.affiliation: Faculty of Science, Josai University, Sakado, Saitama, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Akatsu
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Ohshima
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Yamagishi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishishiro
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Teruo
authors.initials: T
authors.lastname: Kurihara
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Katayama
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shoji
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D052176:Azulenes / Q000737:chemistry / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000737:chemistry / Q000494:pharmacology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D052176:Azulenes; D006846:Hydrocarbons, Halogenated