Effects of a novel trinuclear platinum complex in cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines: interference with cell cycle progression and induction of apoptosis.
We evaluated the effects of the trinuclear platinum complex, BBR 3464, in a human ovarian carcinoma cell line (OAW42) and in its cisplatin (CDDP)-resistant counterpart (OAW42MER). A 14-fold increased sensitivity to a 1-h BBR 3464 exposure was found in OAW42MER cells compared with their parental cell line. Flow cytometric experiments showed that BBR 3464 was able to induce a persistent block of OAW42 and OAW42MER cells in the G2M phase, whereas CDDP caused an initial accumulation of cells in the S phase followed by an increase in the G2M cell fraction in both cell lines. Exposure to equitoxic (IC(50)) drug concentrations induced programmed cell death in both cell lines. However, the percentage of cells with an apoptotic nuclear morphology was slightly higher after CDDP than BBR 3464 treatment in OAW42 cells, whereas the opposite pattern was observed in OAW42MER cells. Degradation of the nuclear lamin B was detected in OAW42 cells after exposure to each drug. Conversely, in OAW42MER cells lamin B cleavage was only appreciable after BBR 3464 exposure. In OAW42 cells, CDDP and BBR 3464 did not appreciably affect the mitochondrial membrane potential (Deltapsi(mt)), whereas in the OAW42MER cell line a marked Deltapsi(mt) reduction was observed after exposure to BBR 3464, but not to CDDP. The results of the study would suggest that the sensitivity to BBR 3464 observed in the CDDP-resistant OAW42MER cell line might be attributable to the ability of the trinuclear platinum complex to modify DNA in a way which is different from that of CDDP and, as a consequence, to induce different cellular responses to DNA damage such as the triggering of specific apoptotic pathways.
Orlandi
L
L
Dipartimento di Oncologia Sperimentale, Unita' Operativa # 10, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133, Milan, Italy.
Colella
G
G
Bearzatto
A
A
Abolafio
G
G
Manzotti
C
C
Daidone
M G
MG
Zaffaroni
N
N
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D019008:Drug Resistance, Neoplasm; D004587:Electrophoresis, Agar Gel; D005260:Female; D006801:Humans; D015151:Immunoblotting; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D009944:Organoplatinum Compounds; D016203:CDC2 Protein Kinase; C114062:BBR 3464