Orlandi L, Colella G, Bearzatto A, Abolafio G, Manzotti C, Daidone M G, Zaffaroni N
Dipartimento di Oncologia Sperimentale, Unita' Operativa # 10, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133, Milan, Italy.
Eur J Cancer. 2001 Mar;37(5):649-59. doi: 10.1016/s0959-8049(00)00445-7.
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.
我们评估了三核铂配合物BBR 3464对人卵巢癌细胞系（OAW42）及其顺铂（CDDP）耐药对应细胞系（OAW42MER）的作用。与亲代细胞系相比，发现OAW42MER细胞对1小时BBR 3464暴露的敏感性增加了14倍。流式细胞术实验表明，BBR 3464能够使OAW42和OAW42MER细胞在G2M期持续阻滞，而CDDP导致细胞在S期初始积累，随后两个细胞系中G2M期细胞比例增加。暴露于等效毒性（IC(50)）药物浓度会诱导两个细胞系发生程序性细胞死亡。然而，在OAW42细胞中，CDDP处理后具有凋亡核形态的细胞百分比略高于BBR 3464处理后，而在OAW42MER细胞中观察到相反的模式。在暴露于每种药物后，在OAW42细胞中检测到核纤层蛋白B的降解。相反，在OAW42MER细胞中，仅在暴露于BBR 3464后核纤层蛋白B的切割才明显。在OAW42细胞中，CDDP和BBR 3464对线粒体膜电位（Deltapsi(mt)）没有明显影响，而在OAW42MER细胞系中，暴露于BBR 3464后观察到明显的Deltapsi(mt)降低，但暴露于CDDP后未观察到。该研究结果表明，在CDDP耐药的OAW42MER细胞系中观察到的对BBR 3464的敏感性可能归因于三核铂配合物以不同于CDDP的方式修饰DNA的能力，因此，诱导对DNA损伤的不同细胞反应，如触发特定的凋亡途径。
