Cisplatin (cDDP) resistance is a matter of concern in triple-negative breast cancer therapeutics. We measured the metabolic response of cDDP-sensitive (S) and -resistant (R) MDA-MB-231 cells to Pd₂Spermine(Spm) (a possible alternative to cDDP) compared to cDDP to investigate (i) intrinsic response/resistance mechanisms and (ii) the potential cytotoxic role of Pd₂Spm. Cell extracts were analyzed by untargeted nuclear magnetic resonance metabolomics, and cell media were analyzed for particular metabolites. CDDP-exposed S cells experienced enhanced antioxidant protection and small deviations in the tricarboxylic acid cycle (TCA), pyrimidine metabolism, and lipid oxidation (proposed cytotoxicity signature). R cells responded more strongly to cDDP, suggesting a resistance signature of activated TCA cycle, altered AMP/ADP/ATP and adenine/uracil fingerprints, and phospholipid biosynthesis (without significant antioxidant protection). Pd₂Spm impacted more markedly on R/S cell metabolisms, inducing similarities to cDDP/S cells (probably reflecting high cytotoxicity) and strong additional effects indicative of amino acid depletion, membrane degradation, energy/nucleotide adaptations, and a possible beneficial intracellular γ-aminobutyrate/glutathione-mediated antioxidant mechanism.

中文翻译：

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Pd2精胺作为顺铂耐药三阴性乳腺癌的替代疗法

顺铂 (cDDP) 耐药性是三阴性乳腺癌治疗中值得关注的问题。我们测量了 cDDP 敏感 (S) 和耐药 (R) MDA-MB-231 细胞对 Pd ₂精胺 (Spm)（cDDP 的可能替代品）与 cDDP 的代谢反应，以研究 (i) 内在反应/耐药性机制和 (ii) Pd ₂ Spm的潜在细胞毒性作用。通过非靶向核磁共振代谢组学分析细胞提取物，并分析细胞培养基中的特定代谢物。暴露于 CDDP 的 S 细胞经历了增强的抗氧化保护和三羧酸循环 (TCA)、嘧啶代谢和脂质氧化（拟议的细胞毒性特征）的小偏差。 R细胞对cDDP反应更强烈，表明激活的TCA循环、改变的AMP/ADP/ATP和腺嘌呤/尿嘧啶指纹以及磷脂生物合成（没有显着的抗氧化保护）的抗性特征。 Pd ₂ Spm 对 R/S 细胞代谢的影响更显着，与 cDDP/S 细胞相似（可能反映了高细胞毒性），并且具有强烈的附加效应，表明氨基酸消耗、膜降解、能量/核苷酸适应以及可能有益的细胞内 γ -氨基丁酸/谷胱甘肽介导的抗氧化机制。