title: Phenothiazine and carbazole-related compounds inhibit mitotic kinesin Eg5 and trigger apoptosis in transformed culture cells.
abstract: The effects of phenothiazine and carbazole derivatives on the cell-cycle progression of human transformed culture cells were analyzed. After 2 days incubation, 5 microM 1-phenethylamino-3-phenothiazin-10-yl-propan-2-ol (1) induced strong mitotic arrest followed by cell death, and 20 microM 1-(3,6-dichloro-9H-carbazol-9-yl)-3-phenethylamino-2-propanol (5) and 1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenethylamino-2-propanol (6) also induced cell death. The TUNEL-positive nuclei characteristic of apoptotic cell death were detected in cells treated with the compounds. We observed beta- and gamma-tubulins in the arrested cells after the addition of compound 1, and found that more than 90% of the mitotic cells exhibited the monoastral spindle instead of the normal bipolar spindle. The inhibitory effects of compounds 1, 5, and 6 on the microtubule-activated ATPase activity of mitotic kinesin Eg5, which is essential for bipolar spindle formation, were obtained. The most effective inhibitor, compound 1, had an IC(50) of 1.52 microM. We also examined their toxicities on various cell lines. Compound 1 had less toxicity with the non-transformed cell line WI-38, whereas it exhibited strong toxicity with the transformed cell lines WI38VA13, HL-60 and HeLa. On the other hand, a high dose of compound 6 caused cell death in both types of culture cells. These results suggest that compound 1, an Eg5 inhibitor, selectively kills transformed culture cells.
authors.affiliation: RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Okumura
authors.forename: Junko
authors.initials: J
authors.lastname: Nakazawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuganezawa
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Takehisa
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D050256:Antimitotic Agents; D002227:Carbazoles; C470243:KIF11 protein, human; D010640:Phenothiazines; C502895:Kif11 protein, rat; D016547:Kinesins