Untargeted metabolomics analysis of omeprazole-enhanced chemosensitivity to cisplatin in mice with non-small cell lung cancer

Abstract

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.

Keywords: Chemosensitivity; Cisplatin; Metabolomics; Non-small cell lung cancer; Omeprazole.