Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Cancer Chemother Pharmacol. 2011 Feb;67(2):401-14. doi: 10.1007/s00280-010-1334-9. Epub 2010 May 5.
To understand the mechanisms behind platinum drug/DENSPM-induced inhibition of cancer cell growth, we compared the effects of oxaliplatin and cisplatin when combined with DENSPM on the induction of SSAT mRNA, activity, polyamines and cell growth in A2780 human ovarian carcinoma cells and their oxaliplatin- and cisplatin-resistant variants A2780/C10B and A2780/CP, respectively.
Parental and Pt-resistant cells were treated with platinum agent alone, DENSPM alone or combination (10 μM each, 20 h). QRT-PCR, radioactive product measurement and HPLC were used for mRNA, activity and polyamine pools, respectively; drug interaction on cell growth was by SRB and isobologram analysis.
Both platinum agents induced SSAT mRNA in parental A2780 cells, but not in resistant cells. Platinum drug/DENSPM combinations produced high levels of SSAT activity in parental cells with significant depletion of spermine and spermidine, but not in resistant cells. Co-treatment with platinum agents increased the levels of DENSPM in all cell lines. Oxaliplatin/DENSPM combination was superior to cisplatin/DENSPM in the inhibition of cell growth in parental cells. No synergy was observed in the resistant cells.
Increased DENSPM levels following co-treatment with Pt agents enhances the translation and stability of SSAT protein leading to polyamine pool depletion, facilitating more Pt-DNA adduct formation in parental cells. Oxaliplatin/DENSPM combination is superior to cisplatin/DENSPM in cell growth inhibition as DACH-Pt DNA adducts are cytotoxic even at relatively fewer numbers. Reduced platinum uptake in Pt-resistant cells contributes to reduced SSAT mRNA induction and absence of synergy when combined with DENSPM.
为了了解铂类药物/DENSPM 抑制癌细胞生长的机制，我们比较了奥沙利铂和顺铂与 DENSPM 联合使用对 SSAT mRNA、活性、多胺和细胞生长的诱导作用，分别在人卵巢癌细胞 A2780 及其奥沙利铂和顺铂耐药变体 A2780/C10B 和 A2780/CP 中。
用铂剂单独、DENSPM 单独或联合（每种 10 μM，20 h）处理亲本和铂耐药细胞。QRT-PCR、放射性产物测量和 HPLC 分别用于 mRNA、活性和多胺池；细胞生长的药物相互作用通过 SRB 和等对图分析。
两种铂剂均诱导亲本 A2780 细胞中的 SSAT mRNA，但在耐药细胞中则不然。铂类药物/DENSPM 联合在亲本细胞中产生高水平的 SSAT 活性，同时显著耗尽精脒和精胺，但在耐药细胞中则不然。联合使用铂剂增加了所有细胞系中 DENSPM 的水平。奥沙利铂/DENSPM 联合在亲本细胞中的细胞生长抑制作用优于顺铂/DENSPM。在耐药细胞中未观察到协同作用。
联合使用铂类药物后 DENSPM 水平升高可增强 SSAT 蛋白的翻译和稳定性，导致多胺池耗竭，从而促进亲本细胞中更多的 Pt-DNA 加合物形成。奥沙利铂/DENSPM 联合在细胞生长抑制方面优于顺铂/DENSPM，因为即使在相对较少的数量下，DACH-Pt DNA 加合物也具有细胞毒性。铂耐药细胞中铂类药物摄取减少导致 SSAT mRNA 诱导减少，与 DENSPM 联合使用时缺乏协同作用。
