Transplatin enhances effect of cisplatin on both single DNA molecules and live tumor cells.
Transplatin enhances effect of cisplatin on both single DNA molecules and live tumor cells.
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DOI：
10.1016/j.abb.2013.04.014
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发表时间：
2013-08
影响因子：
3.9
通讯作者：
Yu-Ru Liu;Chao Ji;Hong-yan Zhang;Shuoxing Dou;P. Xie;Wei-chi Wang;Peng-Ye Wang
中科院分区：
文献类型：
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作者：
Yu-Ru Liu;Chao Ji;Hong-yan Zhang;Shuoxing Dou;P. Xie;Wei-chi Wang;Peng-Ye Wang
顺铂是临床应用的主要铂类抗肿瘤药物。然而，它的类似物，反铂，已知具有无效的抗肿瘤活性。尽管在这一领域进行了深入的研究，但DNA分子与这两种铂配合物反应的结构和生物物理性质还没有完全阐明。在本研究中，我们观察到顺铂加合物附近的DNA发生了有效的交联。高分辨原子力显微镜研究表明，顺铂加合物侧翼核苷酸的交联具有纳米尺度(∼10-60 nm)的杆状扭结环状结构。在活体实验中，顺铂和顺铂联合处理可诱导细胞DNA出现大量较小尺寸的扭结环(∼为15 nm)。此外，与顺铂单独治疗相比，联合治疗导致细胞毒性增强，链间交联量增加，细胞损伤更不愿意细胞修复系统。本研究结果为了解DNA与铂类药物的分步反应提供了新的线索，并可能为开发新的抗肿瘤策略提供基础。
Cisplatin is the main platinum antitumor drug applied in clinical settings. However, itstransisomer, transplatin, is known to have an ineffective antitumor activity. Despite intensive studies in this field, the structural and biophysical properties of DNA molecules reacting with these two platinum complexes have not been fully elucidated. In the present study, we observed that transplatin made efficient cross-linking of DNA in the vicinity of cisplatin adducts. High-resolution atomic force microscopy studies revealed that the transplatin-induced cross-linkings of nucleotides flanking cisplatin adducts were characterized by kinked-loop structures with rod-like shapes of nanometer scales (∼10–60 nm). The results were further confirmed by denaturing gel electrophoresis and single-molecule experiment using magnetic tweezers.In vivostudies revealed that transplatin and cisplatin co-treatment could induce a considerable amount of kinked loops with smaller sizes (∼15 nm) in cellular DNA. Furthermore, compared with cisplatin treatment alone, the co-treatment resulted in enhanced cytotoxicity, increased amount of interstrand cross-links, and cell lesions more reluctant to cellular repair system. The results of the present study provide a new clue for understanding the stepwise reactions of DNA with platinum drugs and might serve as a basis for the development of a new antitumor strategy.