Department of Experimental Therapeutics-1950, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
Cancer Chemother Pharmacol. 2020 Jun;85(6):1129-1140. doi: 10.1007/s00280-020-04085-1. Epub 2020 May 28.
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.
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.
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.
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.
奥沙利铂和沙铂对顺铂耐药肿瘤细胞具有活性。虽然这两种铂类似物结构相关，但奥沙利铂更具活性。因此，进行了专注于蛋白质表达谱分析的研究，以确定抗肿瘤活性差异的分子机制。
我们将顺铂作为参考，并将 DAP 作为奥沙利铂的 Pt(IV)-前药，以抵消沙铂的 Pt(IV)状态，同时在研究中使用了 A2780、顺铂耐药 2780CP/Cl-16、U2OS 和 HCT-116 肿瘤细胞。药物暴露后通过反相蛋白阵列和 Ingenuity 通路分析检查蛋白质表达。通过流式细胞术评估细胞周期，通过生长抑制测定评估细胞毒性，通过 GFP 报告测定评估同源重组 (HR)。
聚类分析将奥沙利铂与 DAP 配对，令人惊讶的是，将沙铂与顺铂配对。这与差异上调 p53/p21 通路相关，与顺铂和沙铂引起的 S 和 G2/M 期阻滞相反，奥沙利铂和 DAP 引起的 G1 期阻滞。此外，奥沙利铂和 DAP 严重下调 Rad51 和 BRCA1，但顺铂和沙铂则不然。结果，仅奥沙利铂和 DAP 抑制 HR，这也导致它们的药物活性超过顺铂和沙铂。
奥沙利铂和 DAP 可强力激活 p53 和 p21，下调 HR 蛋白以增强药物活性。更重要的是，由于奥沙利铂诱导 BRCA 样状态，它可能对 BRCA 阳性癌症具有潜在作用。另一方面，沙铂在蛋白质表达谱上与顺铂相似，这表明化学结构的微小变化可显著改变信号转导途径以调节药物活性。
