TY - JOUR T1 - Tumor-specificity and Type of Cell Death Induced by Trihaloacetylazulenes in Human Tumor Cell Lines JF - Anticancer Research JO - Anticancer Res SP - 133 LP - 143 VL - 27 IS - 1A AU - TAKASHI SEKINE AU - JURI TAKAHASHI AU - MASAYUKI NISHISHIRO AU - ATSUHIRO ARAI AU - HIDETSUGU WAKABAYASHI AU - TERUO KURIHARA AU - MASAKI KOBAYASHI AU - KEN HASHIMOTO AU - HIROTAKA KIKUCHI AU - TADASHI KATAYAMA AU - YUMIKO KANDA AU - SHIRO KUNII AU - NOBORU MOTOHASHI AU - HIROSHI SAKAGAMI Y1 - 2007/01/01 UR - http://ar.iiarjournals.org/content/27/1A/133.abstract N2 - 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. ER -