氧化还原活性MNTNHEX-2-PYP5+和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
影响因子:5.60000
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
摘要
基于氧化还原的癌症治疗策略旨在提高癌细胞中的活性氧（ROS）水平，从而改变其氧化还原状态，并最终诱导细胞死亡。有希望的化合物，称为超氧化物歧化酶模仿（SODM），例如MNTNHEX-2-PY5+（MNTNHEX）可能会在缺乏ROS去除系统的癌细胞中增加细胞内H2O2，从而提高放射性和化学疗法的功效。我们先前已经表明，MNTNHEX是单独的，或与顺铂结合到非小细胞肺癌（NSCLC）细胞。为了更深入地了解该化合物的影响和安全性，分析细胞内发生的代谢改变至关重要。因此，我们的目标是使用基于核磁共振（NMR）基于光谱的代谢组学的NSCLC细胞（A549和H1975）研究NSCLC细胞（A549和H1975）的细胞内代谢组（细胞内代谢产物），以评估MNTNHEX在SESE或CISPLATIN结合使用MntnHex后，评估细胞代谢后的细胞代谢变化。 1H NMR代谢组学显示，与未经处理的细胞（九个失调的代谢产物）相比，A549细胞中有更高数量的明显变化的代谢产物，或与顺铂相比，这表明对氨基氨基na的生物合成，glclycoline syopen syogenencon sypauine contuine conseogenthementy tentauthemencoplatin complatin comenty thaunthemacy glyceline syopen contine comention comention comention themocyl-trna-trna生物合作。甘油磷脂，丙酮酸，精氨酸和脯氨酸代谢。关于H1975细胞，在与MNTNHEX和顺铂共同治疗时观察到六种代谢产物水平的显着变化，表明氨基酰基-TRNA生物合成，精氨酸氨酸，脯氨酸代谢，丙酮酸代谢，丙酮酸代谢，代谢性代谢性和糖溶解/糖类/葡萄干/糖的发生。这些发现有助于我们了解MNTNHEX对NSCLC细胞的影响。重要的是，特定的改变的代谢产物（例如牛磺酸）可能有助于MNTNHEX的化学敏化作用。
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.