title: Cell growth inhibition, G2M cell cycle arrest and apoptosis induced by the imidazoacridinone C1311 in human tumour cell lines.
abstract: The cytotoxic activity of the imidazoacridinone C1311 was assessed on two ovarian cancer cell lines (A2780, OAW42) and one osteogenic sarcoma cell line (U2-OS) and their sublines (A2780Cp8, OAW42-MER and U2-OS-R) with experimentally induced resistance to cisplatin. A 1-h exposure to C1311 significantly inhibited the growth of all cell lines, with IC50 values ranging from 0.50 +/-0.11 to 4.10+/-0.36 microM. No or only partial cross-resistance was found between C1311 and cisplatin in the different cell lines. Treatment with equitoxic (IC50) C1311 concentrations consistently induced accumulation of cells in the G2M phase. The cyclin B1-associated p34(cdc2) kinase activity in cells arrested in G2M was superimposable to that of control cells in the OAW42-MER and U2-OS cell lines, whereas a reduction of cdc2 catalytic activity was observed in OAW42 and U2-OS-R cells. Exposure to C1311 (IC50) induced apoptosis in the U2-OS and U2-OS-R cell lines, whereas in the OAW42 and OAW42-MER cell lines there was a negligible percentage of apoptotic cells. In U2-OS, U2-OS-R and OAW42 cells, C1311 induced an increase in p53 expression and an increase in p21waf1 protein, whereas p53 failed to transactivate p21waf1 in OAW42-MER cells. An almost complete abrogation of bcl-2 was observed in U2-OS-R cells in correspondence with the peak of apoptosis induction. Our results indicate that C1311 is active against human ovarian cancer and osteogenic sarcoma cells and is not cross-resistant with CDDP. Moreover, C1311 blocks cells in the G2M phase and induces apoptosis in a small percentage of osteogenic sarcoma cells.
authors.affiliation: Dipartimento di Oncologia Sperimentale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133, Milan, Italy. zaffaroni@isititutotumori.mi.it
authors.forename: N
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: C
authors.initials: C
authors.lastname: De Marco
authors.forename: R
authors.initials: R
authors.lastname: Villa
authors.forename: S
authors.initials: S
authors.lastname: Riboldi
authors.forename: M G
authors.initials: MG
authors.lastname: Daidone
authors.forename: J A
authors.initials: JA
authors.lastname: Double
mesh_terms: D000609:Aminoacridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D019926:Cyclin B / Q000187:drug effects / Q000378:metabolism; D056744:Cyclin B1; D004305:Dose-Response Relationship, Drug; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D012516:Osteosarcoma / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; C098965:C 1311