title: Tumor-specificity and type of cell death induced by phenoxazines.
abstract: 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.
authors.affiliation: Division of Pharmacology, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
authors.forename: Fumika
authors.initials: F
authors.lastname: Suzuki
authors.forename: Ken
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Mariko
authors.initials: M
authors.lastname: Ishihara
authors.forename: Gunnar
authors.initials: G
authors.lastname: Westman
authors.forename: Kristin
authors.initials: K
authors.lastname: Samuelsson
authors.forename: Masami
authors.initials: M
authors.lastname: Kawase
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D018922:HL-60 Cells; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000473:pathology; D010078:Oxazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010078:Oxazines; C039203:phenoxazine