Cell growth inhibition, G2M cell cycle arrest and apoptosis induced by the imidazoacridinone C1311 in human tumour cell lines.
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.
Zaffaroni
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N
Dipartimento di Oncologia Sperimentale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133, Milan, Italy. zaffaroni@isititutotumori.mi.it
De Marco
C
C
Villa
R
R
Riboldi
S
S
Daidone
M G
MG
Double
J A
JA
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
D000609:Aminoacridines; D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; C098965:C 1311