Cisplatin is a widely used drug in the treatment of various solid tumors, such as ovarian cancer. However, while the acquired resistance significantly limits the success of therapy, some tumors, such as colorectal cancer, are intrinsically insensitive to cisplatin. Only a small amount of intracellular platinum binds to the target—genomic DNA. The fate of the remaining drug is largely obscure. This work aimed to identify the cytosolic protein binding partners of cisplatin in ovarian and colorectal cancer cells and to evaluate their relevance for cell sensitivity to cisplatin and oxaliplatin. Using the fluorescent cisplatin analog BODIPY-cisplatin, two-dimensional gel electrophoresis, and mass spectrometry, we identified the protein binding partners in A2780 and cisplatin-resistant A2780cis ovarian carcinoma, as well as in HCT-8 and oxaliplatin-resistant HCT-8ox colorectal cell lines. Vimentin, only identified in ovarian cancer cells; growth factor receptor-bound protein 2, only identified in colorectal cancer cells; and glutathione-S-transferase π, identified in all four cell lines, were further investigated. The effect of pharmacological inhibition and siRNA-mediated knockdown on cytotoxicity was studied to assess the relevance of these binding partners. The silencing of glutathione-S-transferase π significantly sensitized intrinsically resistant HCT-8 and HCT-8ox cells to cisplatin, suggesting a possible involvement of the protein in the resistance of colorectal cancer cells to the drug. The inhibition of vimentin with FiVe1 resulted in a significant sensitization of A2780 and A2780cis cells to cisplatin, revealing new possibilities for improving the chemosensitivity of ovarian cancer cells.

中文翻译：

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顺铂蛋白结合伙伴及其与铂类药物敏感性的相关性。

顺铂是一种用于治疗各种实体瘤（例如卵巢癌）的药物。然而，尽管获得的耐药性极大地限制了治疗的成功，但某些肿瘤（例如结直肠癌）对顺铂本质上不敏感。只有少量的细胞内铂与靶基因组DNA结合。其余药物的命运在很大程度上是晦涩的。这项工作旨在确定卵巢癌和大肠癌细胞中顺铂的胞浆蛋白结合伴侣，并评估它们对顺铂和奥沙利铂细胞敏感性的相关性。使用荧光顺铂类似物BODIPY-顺铂，二维凝胶电泳和质谱，我们确定了A2780和耐顺铂A2780cis卵巢癌中的蛋白结合伴侣，以及HCT-8和耐奥沙利铂的HCT-8ox结直肠细胞系。波形蛋白，仅在卵巢癌细胞中鉴定；生长因子受体结合蛋白2，仅在结直肠癌细胞中鉴定；并进一步研究了在所有四个细胞系中鉴定出的谷胱甘肽-S-转移酶π。研究了药理学抑制作用和siRNA介导的敲低对细胞毒性的影响，以评估这些结合伴侣的相关性。谷胱甘肽-S-转移酶π的沉默使内在抵抗力的HCT-8和HCT-8ox细胞对顺铂敏感，这表明该蛋白可能参与了结直肠癌细胞对这种药物的抵抗。FiVe1对波形蛋白的抑制作用导致A2780和A2780cis细胞对顺铂具有明显的敏感性，