Purpose

Oxaliplatin and satraplatin demonstrate activity against cisplatin-resistant tumor cells. Although the two platinum analogs are structurally-related, oxaliplatin is more active. Therefore, studies focusing on protein expression profiling were undertaken to identify the molecular mechanism for the difference in antitumor activity.

Methods

We included cisplatin as reference and DAP as a Pt(IV)-prodrug of oxaliplatin to offset Pt(IV) status of satraplatin, and utilized A2780, cisplatin-resistant 2780CP/Cl-16, U2OS, and HCT-116 tumor cells in the investigation. Protein expressions following drug exposures were examined by reverse-phase protein array and ingenuity pathway analysis. Cell cycle was assessed by flow cytometry, cytotoxicity by growth inhibition assay, and homologous recombination (HR) by a GFP reporter assay.

Results

Clustering analysis paired oxaliplatin with DAP and, surprisingly, satraplatin with cisplatin. This correlated with differential upregulation of p53/p21 pathway, with S and G2/M arrests by cisplatin and satraplatin in contrast to G1 arrest by oxaliplatin and DAP. Moreover, Rad51 and BRCA1 were severely downregulated by oxaliplatin and DAP, but not cisplatin and satraplatin. As a result, HR was inhibited only by oxaliplatin and DAP and this also contributed to their greater drug activity over cisplatin and satraplatin.

Conclusions

Oxaliplatin and DAP robustly activate p53 and p21, which downregulate HR proteins to enhance drug activity. More significantly, since oxaliplatin induces a BRCAness state, it may have potential against BRCA-proficient cancers. Satraplatin, on the other hand, resembled cisplatin in its protein expression profile, which indicates that small changes in chemical structure can substantially alter signal transduction pathways to modulate drug activity.

中文翻译：

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蛋白质表达谱鉴定了基于铂的抗肿瘤剂对同源重组的差异调节。

目的

奥沙利铂和沙铂显示出对顺铂耐药肿瘤细胞的活性。尽管两个铂类似物在结构上相关，但奥沙利铂的活性更高。因此，进行了针对蛋白质表达谱的研究，以确定抗肿瘤活性差异的分子机制。

方法

我们将顺铂作为参考，将DAP作为奥沙利铂的Pt（IV）前药以抵消沙铂的Pt（IV）状态，并在其中使用了A2780，耐顺铂2780CP / Cl-16，U2OS和HCT-116肿瘤细胞。调查。通过反相蛋白质阵列和独创性途径分析检查了药物暴露后的蛋白质表达。通过流式细胞术评估细胞周期，通过生长抑制测定法评估细胞毒性，并通过GFP报告基因测定法评估同源重组（HR）。

结果

聚类分析将奥沙利铂与DAP配对，令人惊讶的是沙特铂与顺铂配对。这与p53 / p21途径的差异上调相关，顺铂和沙铂阻止S和G2 / M，而奥沙利铂和DAP阻止G1。此外，Rad51和BRCA1被奥沙利铂和DAP严重下调，但不被顺铂和沙特铂下调。结果，HR仅被奥沙利铂和DAP抑制，这也有助于它们比顺铂和沙铂具有更大的药物活性。

结论

奥沙利铂和DAP强烈激活p53和p21，从而下调HR蛋白以增强药物活性。更重要的是，由于奥沙利铂可诱导BRCAness状态，因此它可能具有抗BRCA能力的癌症。另一方面，沙铂在其蛋白表达谱中与顺铂类似，这表明化学结构的细微变化可实质上改变信号转导途径以调节药物活性。