title: Tumor-specificity and type of cell death induced by trihaloacetylazulenes in human tumor cell lines.
abstract: Twenty trihaloacetylazulene derivatives with one atom of fluorine, chlorine, bromine or iodine was investigated for their tumor-specific cytotoxicity and apoptosis-inducing activity against three human normal cells (gingival fibroblast, HGF; pulp cell, HPC; periodontal ligament fibroblast, HPLF) and four human tumor cell lines (squamous cell carcinoma, HSC-2, HSC-3, HSC-4; promyelocytic leukemia, HL-60). There was no apparent difference in the cytotoxic activity between 2-methoxyazulenes [1a-1e, 2a-2e] and 2-ethoxyazulenes [3a-3e, 4a-4e]. Trichloroacetylazulenes [2a-2e, 4a-4e] generally showed higher cytotoxicity and tumor-specificity (expressed as a TS value) as compared with the corresponding trifluoroacetylazulenes [1a-1e, 3a-3e]. Substitution of chloride [1c, 2c, 3c. 4c], bromide [1d, 2d, 3d, 4d] or iodine [1e, 2e, 3e, 4e] at the C-3 position further enhanced cytotoxic activity against four tumor cell lines, especially HL-60 cells. Among twenty trihaloacetylazulene derivatives, two compounds [2d] and [4c] showed the highest tumor specificity (TS = > 3.5 and > 2.5, respectively). Compounds [2d] and [4c] induced apoptotic cell death characterized by caspase-3, -8 and -9 activation and internucleosomal DNA fragmentation in HL-60 cells. On the other hand, compounds [2d] and [4c] induced autophagic cell death characterized by lower activation of caspases, lack of DNA fragmentation, vacuolization and autophagosome formation detected by acridine orange and LC3-GFP fluorescence, without the decline of the intracellular concentration of three major polyamines in HSC-4 cells. The cytotoxic activity of [4c], but not [2d], was slightly reduced by 3-methyladenine, an inhibitor of autophagy. These results suggest the diversity of cell death type induced in human tumor cell lines by trihaloacetylazulene derivatives.
authors.affiliation: Faculty of Science, Josai University, Sakado, Saitama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekine
authors.forename: Juri
authors.initials: J
authors.lastname: Takahashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishishiro
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Arai
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Teruo
authors.initials: T
authors.lastname: Kurihara
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Ken
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Katayama
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kanda
authors.forename: Shiro
authors.initials: S
authors.lastname: Kunii
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; 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