Department of Pharmacy, The First Hospital of Jilin University, 130021, Changchun, China.
Department of Pharmacy, The First Hospital of Jilin University, 130021, Changchun, China.
Chem Biol Interact. 2022 Jun 1;360:109933. doi: 10.1016/j.cbi.2022.109933. Epub 2022 Apr 18.
Drug resistance of tumors remains a major barrier in cisplatin (CDDP)-based chemotherapy. Omeprazole (OME) is often utilized during chemotherapy to alleviate gastrointestinal symptoms. In a previous investigation, we demonstrated a protective effect of OME against CDDP-induced kidney injury. To further establish whether OME could enhance chemosensitivity to CDDP and the underlying mechanisms, an in vivo tumor-bearing mouse model with CDDP-resistant A549 non-small cell lung cancer (A549/CDDP) was established in the current study. A high-performance liquid chromatography-time of flight mass spectrometry (HPLC-TOF/MS)-based untargeted metabolomics approach for tumor tissue and serum was employed to explore the mechanisms underlying the enhanced therapeutic effects of co-administration of CDDP and OME. Notably, tumor weights of mice in the CDDP + OME group were significantly decreased compared with those treated with CDDP alone. HE and TUNEL staining revealed more significant apoptosis of tumor cells in the group co-administered CDDP + OME relative to CDDP alone. Overexpression of multidrug resistance-associated protein 2 in CDDP-resistant tumors was significantly reversed upon treatment with CDDP + OME. PCA score plots of the groups co-treated with CDDP + OME were clearly separated from those treated with CDDP alone in metabolomics analysis for tumor and serum samples, clearly suggesting that co-administration of OME enhances the antitumor effect of CDDP. Subsequently, 10 and 7 metabolites in CDDP + OME group with significant changes in tumor and serum compared with CDDP group, respectively, were identified. Pathway analysis both in tumor and serum samples revealed regulation of the metabolism of purines, several amino acids and riboflavin in enhanced chemotherapy with both OME and CDDP. The collective findings provide beneficial novel insights into drug-drug interactions, which could improve the application of CDDP in clinical practice.
肿瘤的耐药性仍然是基于顺铂（CDDP）的化疗的主要障碍。奥美拉唑（OME）在化疗中经常被用于缓解胃肠道症状。在之前的研究中，我们证明了 OME 对 CDDP 诱导的肾损伤具有保护作用。为了进一步确定 OME 是否可以增强对 CDDP 的化疗敏感性及其潜在机制，本研究中建立了一种携带 CDDP 耐药性 A549 非小细胞肺癌（A549/CDDP）的荷瘤小鼠模型。采用基于高效液相色谱-飞行时间质谱（HPLC-TOF/MS）的非靶向代谢组学方法对肿瘤组织和血清进行分析，以探讨 CDDP 和 OME 联合给药增强治疗效果的机制。值得注意的是，与单独给予 CDDP 相比，CDDP+OME 组的小鼠肿瘤重量明显降低。HE 和 TUNEL 染色显示，与单独给予 CDDP 相比，CDDP+OME 联合给药组的肿瘤细胞凋亡更为明显。多药耐药相关蛋白 2 在 CDDP 耐药肿瘤中的过度表达在给予 CDDP+OME 治疗后明显逆转。代谢组学分析中，CDDP+OME 联合治疗组的 PCA 得分图与单独给予 CDDP 组明显分离，表明 OME 的联合使用增强了 CDDP 的抗肿瘤作用。随后，在 CDDP+OME 组的肿瘤和血清样本中分别鉴定出 10 种和 7 种代谢物与 CDDP 组相比有明显变化。肿瘤和血清样本中的通路分析均显示，OME 和 CDDP 联合化疗可调节嘌呤、几种氨基酸和核黄素的代谢。这些发现为药物相互作用提供了有益的新见解，可提高 CDDP 在临床实践中的应用。
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