氧化还原活性MnTnHex-2-PyP5+与顺铂对非小细胞肺癌细胞代谢组的影响

Impact of the redox-active MnTnHex-2-PyP5+ and cisplatin on the metabolome of non-small cell lung cancer cells

BIOCHEMICAL PHARMACOLOGY

影响因子:5.6

分区:医学2区 / 药学2区

发表日期:2024 Sep

作者: Rita B Soares, Joana Pinto, Filipa Amaro, Rita Manguinhas, Nuno Gil, Rafael Rosell, Ines Batinic-Haberle, Ana S Fernandes, Nuno G Oliveira, Paula Guedes de Pinho

DOI: 10.1016/j.bcp.2024.116424

摘要

以氧化还原为基础的癌症治疗策略旨在提高癌细胞中的反应性氧物种（ROS）水平，从而改变其氧化还原状态，最终诱导细胞死亡。具有潜力的化合物，如超氧化物歧化酶模拟物（SODm），例如MnTnHex-2-Py5+（MnTnHex），可以增加ROS缺陷系统癌细胞中的细胞内H2O2，增强放疗和化疗的疗效。我们之前已证明，MnTnHex单独或与顺铂联合对非小细胞肺癌（NSCLC）细胞具有细胞毒性。为了深入理解该化合物的作用和安全性，有必要分析细胞内代谢的变化。因此，我们利用核磁共振（NMR）代谢组学，研究了NSCLC细胞（A549和H1975）在暴露于MnTnHex单独或联合顺铂时的细胞代谢变化。1H NMR代谢组学显示，暴露于MnTnHex单独或联合顺铂的A549细胞中，有更多显著变化的代谢物（九种异常代谢物），提示影响氨酰-tRNA生物合成、糖酵解/糖异生、牛磺酸、假牛磺酸、甘油磷脂、丙酮酸、精氨酸和脯氨酸代谢。对于H1975细胞，观察到六种代谢物水平的显著变化，提示氨酰-tRNA生物合成、精氨酸和脯氨酸代谢、丙酮酸代谢和糖酵解/糖异生的紊乱。这些发现有助于理解MnTnHex对NSCLC细胞的影响。特别是，某些特定的变化代谢物，如牛磺酸，可能有助于MnTnHex的化学敏感作用。

Abstract

Redox-based cancer therapeutic strategies aim to raise reactive oxygen species (ROS) levels in cancer cells, thus modifying their redox status, and eventually inducing cell death. Promising compounds, known as superoxide dismutase mimics (SODm), e.g. MnTnHex-2-Py5+ (MnTnHex), could increase intracellular H2O2 in cancer cells with deficient ROS removal systems and therefore enhance radio- and chemotherapy efficacy. We have previously shown that MnTnHex was cytotoxic either alone or combined with cisplatin to non-small cell lung cancer (NSCLC) cells. To gain a deeper understanding of the effects and safety of this compound, it is crucial to analyze the metabolic alterations that take place within the cell. Our goal was thus to study the intracellular metabolome (intracellular metabolites) of NSCLC cells (A549 and H1975) using nuclear magnetic resonance (NMR) spectroscopy-based metabolomics to evaluate the changes in cellular metabolism upon exposure to MnTnHex per se or in combination with cisplatin. 1H NMR metabolomics revealed a higher number of significantly altered metabolites in A549 cells exposed to MnTnHex alone or combined with cisplatin in comparison with non-treated cells (nine dysregulated metabolites), suggesting an impact on aminoacyl-tRNA biosynthesis, glycolysis/gluconeogenesis, taurine, hypotaurine, glycerophospholipid, pyruvate, arginine and proline metabolisms. Regarding H1975 cells, significant alterations in the levels of six metabolites were observed upon co-treatment with MnTnHex and cisplatin, suggesting dysregulations in aminoacyl-tRNA biosynthesis, arginine and proline metabolism, pyruvate metabolism, and glycolysis/gluconeogenesis. These findings help us to understand the impact of MnTnHex on NSCLC cells. Importantly, specific altered metabolites, such as taurine, may contribute to the chemosensitizing effects of MnTnHex.