Apoptosis-inducing Activity of Trihaloacetylazulenes against Human Oral Tumor Cell Lines

• Published in: Anticancer research Vol. 26; no. 3A; pp. 1917 - 1923
• Main Authors: AKATSU, Yoshiaki, OHSHIMA, Nobuharu, NAKASHIMA, Hideki, SAKAGAMI, Hiroshi, YAMAGISHI, Yoshie, NISHISHIRO, Masayuki, WAKABAYASHI, Hidetsugu, KURIHARA, Teruo, KIKUCHI, Hirotaka, KATAYAMA, Tadashi, MOTOHASHI, Noboru, SHOJI, Yuko
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.05.2006
• Subjects: Apoptosis - drug effects; 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; Enzyme; Cysteine endopeptidases; Caspase; Biological activity; Protein; Fragmentation; Peptidases; Oral cavity; Cancerology; Cell death; DNA; Established cell line; DNA fragmentation; Trihaloacetylazulenes; Hydrolases; Tumor; apoptosis-related proteins; Tumor cell; Apoptosis
• ISSN: 0250-7005; 1791-7530

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.