Smyre Christopher L, Saluta Gilda, Kute Timothy E, Kucera Gregory L, Bierbach Ulrich
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States.
ACS Med Chem Lett. 2011 Aug 31;2(11):870-874. doi: 10.1021/ml2001888.
The platinum-acridine anti-cancer agent PtCl(en)(LH)(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 IC(90) 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.
对铂 - 吖啶抗癌剂PtCl(en)(LH)₂（1）（en = 乙二胺，LH = N - (2 - (吖啶 - 9 - 基氨基)乙基)-N - 甲基丙酰亚胺酰胺，吖啶鎓阳离子）和临床药物顺铂在耐化疗的非小细胞肺癌（NSCLC）细胞系中进行了细胞毒性效力和细胞杀伤机制的研究。在测试的三种细胞系（NCI - H460、NCI - H522和NCI - H1435）中，化合物1在达到低纳摩尔范围的抑制浓度下，与顺铂相比显示出40 - 200倍的显著细胞毒性增强。基于通过阻抗测量实时监测的细胞粘附和细胞形态变化，在等毒性浓度下，化合物1杀死NCI - H460细胞的效率明显高于顺铂。对NCI - H460细胞的流式细胞术分析显示，用化合物1处理的细胞出现强烈的S期阻滞，而用顺铂处理的细胞则进入细胞周期的G2/M期。在用化合物1在IC₉₀摩尔浓度处理48小时的NCI - H460细胞中，基于荧光团可点击核苷类似物5 - 乙炔基 - 2'-脱氧尿苷（EdU）掺入新合成DNA的减少，观察到75%的活细胞中DNA复制受到明显抑制。根据该药物的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独特的细胞周期扰动和细胞杀伤潜力。
