Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
J Pharmacol Exp Ther. 2014 Mar;348(3):360-71. doi: 10.1124/jpet.113.210054. Epub 2013 Dec 17.
Since response to platinum-based therapy in non-small-cell lung cancer (NSCLC) is poor, the present study was designed to rationally identify novel drug combinations in cell models including the A549 cell line and the cisplatin-resistant subline A549/Pt, characterized by reduced sensitivity to cisplatin-induced apoptosis and by upregulation of efflux transporters of the ATP binding cassette (ABC) superfamily. Given the molecular features of these cells, we focused on compounds triggering apoptosis through different mechanisms, such as the mitochondria-targeting drug arsenic trioxide and the phenanthridine analog sanguinarine, which induce apoptosis through the extrinsic pathway. Sanguinarine, not recognized by ABC transporters, could overcome cisplatin resistance and, when used in combination with arsenic trioxide, was synergistic in A549 and A549/Pt cells. The arsenic trioxide/sanguinarine cotreatment upregulated genes implicated in apoptosis activation through the extrinsic pathway. Drug combination experiments indicated that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment improved arsenic trioxide/sanguinarine efficacy, a feature associated with a striking apoptosis induction, particularly in the cisplatin-resistant variant. Thus, a synergistic interaction between sanguinarine and arsenic trioxide could be obtained independent of relative cell sensitivity to arsenic trioxide, and an enhanced apoptosis induction could be achieved in combination with TRAIL through modulation of the extrinsic apoptotic pathway. Antitumor activity studies supported the interest of drug combinations including TRAIL in NSCLC, indicating that drug-resistant NSCLC cells can efficiently be killed by the combination of proapoptotic agents. Our results suggest that the molecular changes occurring in treated cells may be exploited to rationally hit surviving cells.
由于非小细胞肺癌 (NSCLC) 对铂类治疗的反应不佳，本研究旨在合理地确定包括 A549 细胞系和对顺铂耐药的 A549/Pt 亚系在内的细胞模型中的新型药物组合，这些细胞的特征是对顺铂诱导的细胞凋亡的敏感性降低，并且 ABC 超家族的外排转运蛋白上调。鉴于这些细胞的分子特征，我们专注于通过不同机制触发细胞凋亡的化合物，如靶向线粒体的三氧化二砷和诱导细胞凋亡通过外在途径的菲啶类似物血根碱。血根碱不被 ABC 转运蛋白识别，可克服顺铂耐药性，并且当与三氧化二砷联合使用时，在 A549 和 A549/Pt 细胞中具有协同作用。三氧化二砷/血根碱共处理上调了通过外在途径激活细胞凋亡的基因。药物组合实验表明，肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 治疗可改善三氧化二砷/血根碱的疗效，这一特征与明显的细胞凋亡诱导相关，尤其是在顺铂耐药的变体中。因此，血根碱和三氧化二砷之间的协同相互作用可以独立于相对细胞对三氧化二砷的敏感性获得，并且通过调节外在凋亡途径，与 TRAIL 联合使用可以实现增强的细胞凋亡诱导。抗肿瘤活性研究支持包括 TRAIL 的药物组合在 NSCLC 中的应用，表明耐药性 NSCLC 细胞可以通过促凋亡剂的组合有效地被杀死。我们的结果表明，在处理细胞中发生的分子变化可被合理利用来靶向存活细胞。
