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[摘要]：The platinum acridine anticancer agent [PtCl(en)(LH)] (NO(3))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 nonsmall 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 as compared to cisplatin at inhibitory concentrations reaching the low nanomolar range. On the basis of 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. |
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