Inhibition of DNA Synthesis by a Platinum-Acridine Hybrid Agent Leads to Potent Cell Kill in Non-Small Cell Lung Cancer.
Inhibition of DNA Synthesis by a Platinum-Acridine Hybrid Agent Leads to Potent Cell Kill in Non-Small Cell Lung Cancer.
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DOI：
10.1021/ml2001888
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发表时间：
2011-08-31
影响因子：
4.2
通讯作者：
Bierbach, Ulrich
中科院分区：
文献类型：
--
作者：
Smyre, Christopher L.;Saluta, Gilda;Kute, Timothy E.;Kucera, Gregory L.;Bierbach, Ulrich
研究了铂-吖啶抗癌剂[PtCl（en）（LH）]（NO3）2（1）（en =乙烷-1，2-二胺，LH = N-（2-（吖啶-9-基氨基）乙基）-N-甲基丙脒，吖啶阳离子）和临床药物顺铂在化疗耐药的非小细胞肺癌（NSCLC）细胞系中的细胞毒性效力和细胞杀伤机制。在测试的三种细胞系（NCI-H460、NCI-H522和NCI-H1435）中，在达到低纳摩尔范围的抑制浓度下，化合物1显示出与顺铂相比40-200倍的显著细胞毒性增强。基于通过阻抗测量真实的时间监测的细胞粘附和细胞形态的变化，化合物1在等毒性浓度下比顺铂显著更有效地杀死NCI-H460细胞。NCI-H460细胞的流式细胞术分析揭示了用化合物1处理的细胞的稳健的S期停滞，而用顺铂处理的细胞进展到细胞周期的G2/M。在用化合物1以IC 90摩尔浓度处理48小时的NCI-H460细胞中观察到75%的活细胞中DNA复制的显著抑制，这是基于荧光团可点击的核苷类似物5-乙炔基-2 ′-脱氧尿苷（EdU）掺入新合成的DNA中的减少。根据该试剂的DNA相互作用及其克服NSCLC中顺铂耐药性的潜力，讨论了化合物1的独特细胞周期扰动和细胞杀伤潜力。
The platinum–acridine anti-cancer agent [PtCl(en)(LH)](NO3)2 (1) (en = ethane-1,2-diamine, LH = N-(2-(acridin-9-ylamino)ethyl)-N-methylpropionimidamide, acridinium cation) and the clinical drug cisplatin were studied in chemoresistant non-small cell lung cancer (NSCLC) cell lines for their cytotoxic potency and cell-kill mechanisms. In the three cell lines tested (NCI-H460, NCI-H522, and NCI-H1435) compound 1 shows a pronounced cytotoxic enhancement of 40–200-fold compared to cisplatin at inhibitory concentrations reaching the low-nanomolar range. Based on changes in cell adhesion and cell morphology, monitored in real time by impedance measurements, compound 1 kills NCI-H460 cells significantly more efficiently than cisplatin at equitoxic concentrations. Flow cytometry analysis of NCI-H460 cells reveals a robust S-phase arrest of cells treated with compound 1, whereas cells treated with cisplatin progress to G2/M of the cell cycle. A pronounced inhibition of DNA replication in 75% of viable cells is observed in NCI-H460 cells treated with compound 1 at an IC90 molar concentration for 48 h, based on the reduced incorporation of the fluorophore-clickable nucleoside analogue 5-ethynyl-2´-deoxyuridine (EdU) into newly synthesized DNA. The distinct cell-cycle perturbations and cell-kill potential of compound 1 are discussed in the light of the DNA interactions of this agent and its potential to overcome cisplatin resistance in NSCLC.
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影响因子：
7.3
作者：
Ma Z;Choudhury JR;Wright MW;Day CS;Saluta G;Kucera GL;Bierbach U
通讯作者：
Bierbach U
影响因子：
4.7
作者：
He G;Kuang J;Khokhar AR;Siddik ZH
通讯作者：
Siddik ZH
影响因子：
8.8
作者：
O'Neill, C F;Ormerod, M G;Robertson, D;Titley, J C;Cumber-Walsweer, Y;Kelland, L R
通讯作者：
Kelland, L R
影响因子：
7.3
作者：
Martins, ET;Baruah, H;Bierbach, U
通讯作者：
Bierbach, U
影响因子：
11.5
作者：
Martin, Lainie P.;Hamilton, Thomas C.;Schilder, Russell J.
通讯作者：
Schilder, Russell J.