title: Inhibition of cyclin D1 expression and induction of apoptosis by inostamycin in small cell lung carcinoma cells.
abstract: Previously, we demonstrated that inostamycin, an inhibitor of phosphatidylinositol turnover, caused cell cycle arrest at the G1 phase, inhibiting the expression of cyclins D1 and E in normal cells. In the present study, we examined the effects of inostamycin on cell cycle progression and apoptosis in human small cell lung carcinoma Ms-1 cells. Treatment of exponentially proliferating Ms-1 cells with low concentrations of inostamycin caused cells to accumulate in the G1 phase. We found that inostamycin decreased cyclin D1, and increased cyclin-dependent kinase inhibitors such as p21WAF1 and p27KIP1 in Ms-1 cells. On the other hand, higher concentrations of inostamycin induced morphological apoptosis and DNA fragmentation in Ms-1 cells without affecting the expression of p53, Bcl-2 and Bax. Inostamycin-induced apoptosis was suppressed by an inhibitor of caspase-3, and a 17 kDa fragment of activated caspase-3 was detected following inostamycin treatment. Therefore, caspase-3(-like) would appear to be involved in inostamycin-induced apoptosis. On the other hand, an inhibitor of caspase-3(-like) proteases did not affect the inhibitory effect of inostamycin on cyclin D1 expression, suggesting that caspase-3(-like) proteases were not responsible for inostamycin-induced G1 arrest.
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama.
authors.forename: M
authors.initials: M
authors.lastname: Imoto
authors.forename: K
authors.initials: K
authors.lastname: Tanabe
authors.forename: S
authors.initials: S
authors.lastname: Simizu
authors.forename: E
authors.initials: E
authors.lastname: Tashiro
authors.forename: M
authors.initials: M
authors.lastname: Takada
authors.forename: K
authors.initials: K
authors.lastname: Umezawa
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis; D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D005663:Furans / Q000494:pharmacology; D006801:Humans; D007399:Interphase / Q000187:drug effects; D008175:Lung Neoplasms / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D005663:Furans; C071861:inostamycin; D019938:Cyclin D1; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases