Tumor-specificity and Type of Cell Death Induced by Phenoxazines

• Published in: Anticancer research Vol. 27; no. 6B; pp. 4233 - 4238
• Main Authors: SUZUKI, Fumika, HASHIMOTO, Ken, ISHIHARA, Mariko, WESTMAN, Gunnar, SAMUELSSON, Kristin, KAWASE, Masami, MOTOHASHI, Noboru, SAKAGAMI, Hiroshi
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.11.2007
• Subjects: Antineoplastic Agents - pharmacology; Biological and medical sciences; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; caspase; cell death; Cell Death - drug effects; Cell Line, Tumor; Chemical Engineering; cytotoxicity; Drug Screening Assays, Antitumor; Fibroblasts - cytology; Fibroblasts - drug effects; Glioblastoma - drug therapy; Glioblastoma - pathology; HL-60 Cells; Humans; INDUCED APOPTOSIS; INHIBITORS; Kemiteknik; KETONES; LINES; Medical sciences; Mouth Neoplasms - drug therapy; Mouth Neoplasms - pathology; Oxazines - pharmacology; phenoxazines; POTENT; Tumors; type of cell death; Enzyme; Cysteine endopeptidases; type of cell death; Caspase; Cytotoxicity; Peptidases; Cancerology; Type specificity; Cell death; Hydrolases; Phenoxazines; Tumor cell; Apoptosis
• ISSN: 0250-7005; 1791-7530; 1791-7530

Phenoxazines have shown diverse biological activities, but tumor-specific cytotoxic activity has not been investigated. A total of 24 phenoxazine derivatives ( WM1-24 ) was investigated for their relative cytotoxicity against human tumor cell lines vs. normal cells. WM7 and WM8 showed the highest tumor-specificity index of 4.3 and 4.8, respectively. Considerable difference in drug-sensitivity was found among these tumor cell lines. Human promyelocytic leukemia HL-60 cells showed the highest sensitivity to both WM7 and WM8 , followed by human oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4), and human gingival fibroblast (HGF), pulp cell (HPC) and periodontal ligament fibroblast (HPLF) were the most resistant. WM7 and WM8 induced little or no internucleosomal DNA fragmentation, and activated caspase-3 in HSC-2, HSC-4 and human glioblastoma T98G cells. These compounds failed to induce autophagic cell death, as judged by acridine orange and microtubule-associated protein 1 light chain 3 (LC3)-GFP assays. These results suggested that the higher cytotoxicity of WM7 and WM8 are derived from the positively-charged quaternary nitrogen substituents on the phenoxazine ring and the electron density of nitrogen at N12, and that inhibition of autophagy is not always coupled with apoptosis induction.