Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Rm. 2108, Bethesda, MD 20892, USA.
Pharmacol Rev. 2012 Jul;64(3):706-21. doi: 10.1124/pr.111.005637. Epub 2012 Jun 1.
Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.
顺铂是最有效的广谱抗癌药物之一。它的有效性似乎归因于顺铂的独特性质，顺铂通过多种途径进入细胞，并在启动细胞自我防御系统的同时形成多种不同的 DNA-铂加合物，通过激活或沉默各种不同的基因，导致明显的表观遗传和/或遗传改变。因此，体内和体外人类癌细胞对顺铂的耐药性的发展必然源于基因表达和蛋白质定位改变的复杂遗传和表观遗传变化。大量已发表的证据表明，在对这种有毒金属化合物产生耐药性的过程中，经常会检测到多效性的改变。几乎每一种支持细胞存活的机制都会发生变化，包括促进细胞生长的途径、细胞凋亡、发育途径、DNA 损伤修复和内吞作用。一般来说，数十个基因在顺铂耐药细胞中受到影响，包括铜代谢途径以及改变细胞骨架、改变蛋白质细胞表面呈现和调节上皮-间充质转化的转录途径。积累减少是导致顺铂耐药的最常见特征之一。这似乎是许多表观遗传和遗传变化导致细胞表面结合位点和/或顺铂转运体丢失以及液相反噬作用减少的结果。
