Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA.
Cell Cycle. 2012 Mar 1;11(5):963-73. doi: 10.4161/cc.11.5.19447.
Despite the clinical success of platinum-containing drugs in the treatment of solid tumors, acquired resistance remains a major obstacle. We previously identified a group of novel transplanaramine or transplatinum compounds based on distinct activity profiles in the NCI-60 panel. In the present study, parental KB-3.1 cells with wild-type p53 and its cisplatin- and oxaliplatin-resistant sublines harboring mutant p53 proteins were used to contrast several transplatinum compounds with cisplatin and oxaliplatin. The transplatinum compounds retained cytotoxic activity in the resistant cell lines. While intracellular accumulation and DNA platination of cisplatin and oxaliplatin was decreased in the resistant cells, the transplatinum compounds both accumulated intracellularly and platinated DNA at comparable levels in all cell lines. Cytoflow analysis confirmed that cisplatin and oxaliplatin alter the cell cycle distribution and result in apoptosis; however, at comparably toxic concentrations, the transplatinum compounds did not alter the cell cycle distribution. Analysis of the cytoplasmic fraction treated with acetone showed that cisplatin and oxaliplatin readily bound to macromolecules in the pellet, whereas a larger percentage of the transplatinum compounds remained in the supernatant. We concluded that, distinct from platinum compounds currently in use, transplatinum compounds accumulate intracellularly in resistant cells at levels comparable to those in drug-sensitive cells, do not affect the cell cycle and thus retain cytotoxicity independent of p53 status and likely have cytoplasmic targets that are important in their activity.
尽管含铂药物在治疗实体瘤方面取得了临床成功，但获得性耐药仍是一个主要障碍。我们之前根据 NCI-60 小组中不同的活性特征，确定了一组新型的平面胺或 transplatinum 化合物。在本研究中，我们使用具有野生型 p53 的亲本 KB-3.1 细胞及其携带突变 p53 蛋白的顺铂和奥沙利铂耐药亚系来对比几种 transplatinum 化合物与顺铂和奥沙利铂。transplatinum 化合物在耐药细胞系中保持细胞毒性活性。虽然顺铂和奥沙利铂在耐药细胞中的细胞内积累和 DNA 铂化作用降低，但 transplatinum 化合物在所有细胞系中均以相似的水平在细胞内积累并铂化 DNA。细胞流式分析证实，顺铂和奥沙利铂改变细胞周期分布并导致细胞凋亡；然而，在可比的毒性浓度下，transplatinum 化合物不会改变细胞周期分布。用丙酮处理的细胞质部分分析表明，顺铂和奥沙利铂容易与沉淀中的大分子结合，而 transplatinum 化合物的较大比例仍留在上清液中。我们得出结论，与目前使用的铂化合物不同，transplatinum 化合物在耐药细胞中以与药物敏感细胞相当的水平在细胞内积累，不影响细胞周期，因此独立于 p53 状态保留细胞毒性，并且可能具有细胞质靶标在其活性中很重要。
