Aspirin Reduces Plasma Concentrations of the Oncometabolite 2-Hydroxyglutarate: Results of a Randomized, Double-Blind, Crossover Trial.
Aspirin Reduces Plasma Concentrations of the Oncometabolite 2-Hydroxyglutarate: Results of a Randomized, Double-Blind, Crossover Trial.
复制标题
DOI：
10.1158/1055-9965.epi-15-0697
复制
发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Ulrich CM
中科院分区：
文献类型：
--
作者：
Liesenfeld DB;Botma A;Habermann N;Toth R;Weigel C;Popanda O;Klika KD;Potter JD;Lampe JW;Ulrich CM
使用阿司匹林是结直肠癌化学预防的有效策略，即使是低剂量也是如此。然而，为了实施阿司匹林干预措施，需要更好地定义风险效益平衡和生物学机制；为了进一步实现这一目标，我们使用了代谢组学方法。我们对 40 名 20-45 岁健康、不吸烟的男性和女性进行了代谢分析，他们参加了一项随机、双盲、交叉试验，每天服用 325 毫克阿司匹林，为期 60 天。在阿司匹林和安慰剂干预后，使用气相和液相色谱-质谱法全面分析参与者的血浆样本。总共测量了 363 种代谢物，涵盖了大多数人类生化途径。与安慰剂治疗的参与者相比，男性和女性在接受阿司匹林治疗后，致癌代谢物 2-羟基戊二酸 (R+S) 的血浆浓度均下降 (p = 0.005)。在使用每次分割中 80% 的样本对数据进行 20 倍随机分割期间，该信号被证明是稳健的。随后，我们在人结直肠癌细胞系中使用靶向、对映特异性检测进行了功能性后续研究，并观察到阿司匹林诱导的 (R)-2-羟基戊二酸减少。我们进一步表明，阿司匹林的主要代谢物水杨酸盐抑制羟基酸-含氧酸转氢酶（HOT）介导的（R）-2-羟基戊二酸的产生，从而为临床观察到的阿司匹林对总2-羟基戊二酸的影响提供了机制证据。使用代谢组学方法和功能随访，我们提出致癌代谢物 (R)-2-羟基戊二酸的减少可能会确定阿司匹林或其代谢物预防癌症的另一个机制。致癌代谢物 (R)-2-羟基戊二酸的减少确定了阿司匹林的一种新的、非 COX 抑制介导的机制。
Aspirin use is an effective strategy for the chemoprevention of colorectal cancer, even at low doses. However, in order to implement aspirin interventions, risk–benefit balances and biological mechanisms need to be better defined; to further this aim, we used a metabolomics approach. We metabolically profiled 40 healthy, non-smoking men and women aged 20–45 years enrolled in a randomized, double-blind, crossover trial of 325 mg aspirin/d over 60 days. Gas and liquid chromatography–mass spectrometry were used to comprehensively profile participants’ plasma samples after aspirin and placebo interventions. A total of 363 metabolites, covering most human biochemical pathways, were measured. Compared to placebo-treated participants, plasma concentrations of the oncometabolite 2-hydroxyglutarate (R+S) decreased after aspirin treatment in both men and women (p = 0.005). This signal proved robust during 20-fold random splitting of the data using 80% of the samples in each split. We subsequently performed functional follow-up studies using targeted, enantiospecific detection in human colorectal cancer cell lines and observed an aspirin-induced reduction of (R)-2-hydroxyglutarate. We further showed that salicylate, the primary aspirin metabolite, inhibits the hydroxyacid–oxoacid transhydrogenase (HOT) mediated production of (R)-2-hydroxyglutarate, thereby providing mechanistic evidence for the clinically observed effects of aspirin on total-2-hydroxyglutarate. Using a metabolomics approach with functional follow-up, we propose that a decrease in the oncometabolite (R)-2-hydroxyglutarate may identify an additional mechanism for aspirin or its metabolites in cancer prevention. Reduction of the oncometabolite (R)-2-hydroxyglutarate identifies a novel, non-COX-inhibition-mediated mechanism of aspirin.