RT Journal Article
SR Electronic
T1 Tumor-specificity and Type of Cell Death Induced by Trihaloacetylazulenes in Human Tumor Cell Lines
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 133
OP 143
VO 27
IS 1A
A1 SEKINE, TAKASHI
A1 TAKAHASHI, JURI
A1 NISHISHIRO, MASAYUKI
A1 ARAI, ATSUHIRO
A1 WAKABAYASHI, HIDETSUGU
A1 KURIHARA, TERUO
A1 KOBAYASHI, MASAKI
A1 HASHIMOTO, KEN
A1 KIKUCHI, HIROTAKA
A1 KATAYAMA, TADASHI
A1 KANDA, YUMIKO
A1 KUNII, SHIRO
A1 MOTOHASHI, NOBORU
A1 SAKAGAMI, HIROSHI
YR 2007
UL http://ar.iiarjournals.org/content/27/1A/133.abstract
AB 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.