Instituto de Investigación Biomédica de Salamanca-IBSAL, 37007 Salamanca, Spain.
Pharmacol Ther. 2012 Oct;136(1):35-55. doi: 10.1016/j.pharmthera.2012.07.003. Epub 2012 Jul 14.
Cisplatin is a chemotherapeutic drug widely used against a variety of cancers. Its clinical utility is severely limited by its toxicity, which mainly affects, but is not limited to, the inner ear and renal tubules. Cisplatin toxicity is determined by target tissue and cell accumulation, subcellular handling and trafficking through diverse subcellular structures, and interaction with macromolecules. Cisplatin accumulates and stresses different organelles from which delay signaling is activated, including mitochondria, lysosomes, the endoplasmic reticulum, the nucleus, the cell membrane and cytoskeleton, and can also be found in the cytosol. This article critically summarizes the available information in order to establish the connection among its known subcellular effects in a hierarchical and integrative framework. Cisplatin causes different types of cell death in a concentration-dependent manner. Knowledge of the events and signaling leading to the different phenotypes is also intertwined within the model, within the scope of the potential utility of this information in the improvement of the pharmacotoxicological profile of this drug. Perspectives for the key aspects that need to be addressed by future investigation are also outlined.
顺铂是一种广泛用于治疗多种癌症的化疗药物。但其毒性严重限制了其临床应用，主要影响但不限于内耳和肾小管。顺铂的毒性取决于靶组织和细胞的积累、亚细胞处理以及通过多种亚细胞结构的运输，以及与大分子的相互作用。顺铂从不同的细胞器中积累并产生应激，这些细胞器包括线粒体、溶酶体、内质网、核、细胞膜和细胞骨架，也可以在细胞质中找到。本文批判性地总结了现有信息，以便在分层和综合的框架内建立其已知的亚细胞作用之间的联系。顺铂以浓度依赖的方式引起不同类型的细胞死亡。导致不同表型的事件和信号通路的知识也交织在该模型中，该模型的范围涵盖了在改善该药物的药毒理学特征方面利用这些信息的潜力。本文还概述了未来研究需要解决的关键方面。
