Tumor-specificity and Type of Cell Death Induced by Trihaloacetylazulenes in Human Tumor Cell Lines

• Published in: Anticancer research Vol. 27; no. 1A; pp. 133 - 143
• Main Authors: SEKINE, Takashi, TAKAHASHI, Juri, KANDA, Yumiko, KUNII, Shiro, MOTOHASHI, Noboru, SAKAGAMI, Hiroshi, NISHISHIRO, Masayuki, ARAI, Atsuhiro, WAKABAYASHI, Hidetsugu, KURIHARA, Teruo, KOBAYASHI, Masaki, HASHIMOTO, Ken, KIKUCHI, Hirotaka, KATAYAMA, Tadashi
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.01.2007
• Subjects: Apoptosis - drug effects; Apoptosis - physiology; Autophagy - drug effects; Autophagy - physiology; Azulenes - chemistry; Azulenes - pharmacology; Biological and medical sciences; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Cell Line; Cell Line, Tumor; Drug Screening Assays, Antitumor; Fibroblasts - cytology; Fibroblasts - drug effects; HL-60 Cells; Humans; Hydrocarbons, Halogenated - chemistry; Hydrocarbons, Halogenated - pharmacology; Medical sciences; Mouth Neoplasms - drug therapy; Mouth Neoplasms - pathology; Structure-Activity Relationship; Tumors; Human; autophagy; Enzyme; Cysteine endopeptidases; vacuolization; Caspase; Fragmentation; Peptidases; Cancerology; Type specificity; Cell death; DNA; Established cell line; DNA fragmentation; Trihaloacetylazulenes; Hydrolases; Tumor cell; Apoptosis
• ISSN: 0250-7005; 1791-7530

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.