基于代谢组学研究胸腺肽α1对非小细胞肺癌裸鼠模型的作用及机制

The metabolomics study of thymosin α1 in non-small cell lung cancer nude mice model

目的基于超高效液相色谱-串联Orbitrap质谱(UHPLC-Q/Exactive)的代谢组学技术研究胸腺肽α1对顺铂化疗的非小细胞肺癌(NSCLC)裸鼠的保护作用。方法将12只裸鼠完全随机分为对照组、顺铂组和顺铂加胸腺肽α1组,每组4只。构建肺癌移植瘤模型,在顺铂组和顺铂加胸腺肽α1组中,腹腔内注射顺铂或顺铂加胸腺肽α1,对照组注射等量的磷酸盐缓冲液。收集裸鼠的血浆样品,进行非靶向代谢组学分析。结合模式识别分析各组间代谢物差异,并评价胸腺肽α1的化疗保护作用。结果胸腺肽α1联合顺铂给药能显著缓解因顺铂引起的裸鼠体质量降低不良反应,顺铂组裸鼠体质量低于对照组[(16.6±0.9) g比(20.1±1.7) g],差异有统计学意义(P <0.05),顺铂加胸腺肽α1组体质量[(21.3±1.3) g]与对照组差异无统计学意义(P> 0.05)。共鉴定出11个生物标记物(氨基乙基磷酸、二十碳二烯酸、柠檬酸等)在顺铂加胸腺肽α1组出现不同程度的回调。结论胸腺肽α1可改善顺铂化疗导致的代谢物紊乱,从而产生化疗保护作用。其机制可能涉及饱和脂肪酸及不饱和脂肪酸生物合成代谢、柠檬酸循环代谢、嘌呤代谢等通路。

Objective To investigate the protective effect of thymosin α1 on cisplatin chemotherapy in non-small cell lung cancer( NSCLC) nude mice by metabolomic techniques based on ultra performance liquid chromatography-tandem Orbitrap mass spectrometry( UHPLC-Q/Exactive). Methods Twelve nude mice were randomly divided into control group,cisplatin group and cisplatin plus thymosin α1 group,with 4 mice in each group. A lung cancer xenograft model was set up. Cisplatin was injected intraperitonealiy in cisplatin group and cisplatin plus thymosin α1 group;thymosin α1 was injected intraperitonealiy in cisplatin plus thymosin α1 group;equivalent phosphate buffer was injected intraperitonealiy in control group. Plasma samples from nude mice were collected for non-targeted metabolomics analysis. The differences in metabolome between groups were analyzed;the chemoprotective effect of thymosin α1 was evaluated. Results The administration of thymosin α1 combined with cisplatin significantly affected the side effects of weight loss in nude mice caused by cisplatin. The body mass of cisplatin group was lower than that of the control group [( 16. 6 ± 0. 9) g vs( 20. 1 ± 1. 7) g]( P < 0. 05);there was no significant difference between cisplatin plus thymosin α1 group [( 21. 3 ± 1. 3) g] and the control group( P > 0. 05). A total of 11 biomarkers showed significant callbacks in cisplatin plus thymosin α1 group.Conclusions Thymosin α1 can improve metabolite disorders caused by cisplatin chemotherapy. The mechanism may involve biosynthesis and metabolism of saturated fatty acids,unsaturated fatty acids,citrate cyclic metabolism and purine metabolism pathways.