Combination effects of platinum drugs and N1, N11 diethylnorspermine on spermidine/spermine N1-acetyltransferase, polyamines and growth inhibition in A2780 human ovarian carcinoma cells and their oxaliplatin and cisplatin-resistant variants.
Combination effects of platinum drugs and N1, N11 diethylnorspermine on spermidine/spermine N1-acetyltransferase, polyamines and growth inhibition in A2780 human ovarian carcinoma cells and their oxaliplatin and cisplatin-resistant variants.
复制标题
DOI：
10.1007/s00280-010-1334-9
复制
发表时间：
2011-02
影响因子：
3
通讯作者：
Pendyala, Lakshmi
中科院分区：
文献类型：
--
作者：
Tummala, Ramakumar;Diegelman, Paula;Hector, Suzanne;Kramer, Debora L.;Clark, Kimberly;Zagst, Patricia;Fetterly, Gerald;Porter, Carl W.;Pendyala, Lakshmi
为了了解铂类药物/DENSPM诱导的癌细胞生长抑制的机制，我们比较了奥沙利铂和顺铂与DENSPM联合使用时对A2780人卵巢癌细胞及其奥沙利铂和顺铂耐药变体A2780/C10 B和A2780/CP中SSAT mRNA、活性、多胺和细胞生长的诱导作用。亲本和Pt抗性细胞用铂剂单独、DENSPM单独或组合（各10 μM，20 h）处理。分别采用QRT-PCR、放射性产物测量和HPLC分析mRNA、活性和多胺库;通过SRB和等效线图分析药物相互作用对细胞生长的影响。两种铂剂诱导SSAT mRNA在亲本A2780细胞，但不耐药细胞。铂类药物/DENSPM组合在亲本细胞中产生高水平的SSAT活性，精胺和亚精胺显著耗竭，但在耐药细胞中不产生。与铂剂的共处理增加了所有细胞系中的DENSPM水平。奥沙利铂/DENSPM组合在抑制亲本细胞中的细胞生长方面优于顺铂/DENSPM上级。在抗性细胞中未观察到协同作用。与Pt试剂共处理后增加的DENSPM水平增强了SSAT蛋白的翻译和稳定性，导致多胺池耗尽，促进亲本细胞中更多Pt-DNA加合物的形成。奥沙利铂/DENSPM组合在细胞生长抑制方面上级顺铂/DENSPM，因为DACH-Pt DNA加合物即使在相对较少的数量下也具有细胞毒性。铂耐药细胞中铂摄取的减少有助于减少SSAT mRNA诱导，并且当与DENSPM组合时缺乏协同作用。
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.
登录
查看更多内容
影响因子：
3
作者：
Hector, Suzanne;Tummala, Ramakumar;Pendyala, Lakshmi
通讯作者：
Pendyala, Lakshmi
影响因子：
2.9
作者：
FogelPetrovic, M;Vujcic, S;Porter, CW
通讯作者：
Porter, CW
影响因子：
5.7
作者：
Allen, Wendy L.;McLean, Estelle G.;Johnston, Patrick G.
通讯作者：
Johnston, Patrick G.
影响因子：
9.7
作者：
Hawthorne, TR;Austin, JK
通讯作者：
Austin, JK
DOI：
10.1016/s1357-2725(03)00174-2
发表时间：
2004-01-01
影响因子：
4
作者：
Marverti, G;Monti, MG;Moruzzi, MS
通讯作者：
Moruzzi, MS