Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials.
Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials.
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DOI：
10.1186/s12967-022-03809-6
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发表时间：
2022-12-29
影响因子：
7.4
通讯作者：
Gandini, Sara
中科院分区：
文献类型：
--
作者：
Bellerba, Federica;Chatziioannou, Anastasia Chrysovalantou;Jasbi, Paniz;Robinot, Nivonirina;Keski-Rahkonen, Pekka;Trolat, Amarine;Vozar, Beatrice;Hartman, Sheri J.;Scalbert, Augustin;Bonanni, Bernardo;Johansson, Harriet;Sears, Dorothy D.;Gandini, Sara
肥胖是乳腺癌幸存者的主要健康问题，与癌症治疗期间的高复发率和疗效降低有关。二甲双胍治疗与降低乳腺癌发病率、复发率和死亡率有关。为了更好地了解二甲双胍可能降低复发的潜在机制，我们的目的是在二甲双胍治疗前后对超重/肥胖乳腺癌幸存者进行代谢分析。在基线、6个月后（Reach For Health试验）和12个月后（MetBreCS试验），从373名随机分配至二甲双胍（n = 194）或安慰剂（n = 179）组的超重或肥胖乳腺癌幸存者中采集空腹血浆样本。使用三种互补方法同时分析存档样品：非靶向LC-QTOF-MS代谢组学、靶向LC-MS代谢组学（AbsoluteIDQ p180，Biocrates）和气相色谱磷脂脂肪酸测定。使用多变量线性回归模型和全族误差校正来鉴定二甲双胍治疗后显著变化的代谢物。基线和研究终点样本均可用的参与者（n = 352）被纳入分析。在调整混杂因素（如研究中心、年龄、体重指数和错误发现率）后，我们发现二甲双胍治疗与瓜氨酸、精氨酸、酪氨酸、咖啡因、副黄嘌呤和茶碱水平降低以及亮氨酸、异亮氨酸、脯氨酸、3-甲基-2-氧代戊酸、4-甲基-2-氧代戊酸、丙氨酸和硫酸吲哚酚水平升高显著相关。二甲双胍治疗后，长链不饱和磷脂酰胆碱（PC ae C36：4、PC ae C38：5、PC ae C36：5和PC ae C38：6）显著降低，磷脂衍生的长链n-6脂肪酸也是如此。二甲双胍治疗的代谢组学特征表明，已知可损害癌细胞生长的特定生化途径发生变化，包括CYP 1A 2活化、脂肪酸去饱和酶活性改变和特定氨基酸代谢改变，包括支链氨基酸催化剂受损。我们在超重乳腺癌幸存者中的研究结果确定了二甲双胍治疗的新代谢效应，这些效应可能在机制上有助于降低该人群的复发风险，并降低观察性研究中报告的肥胖相关癌症风险。ClinicalTrials.gov标识符：NCT 01302379和EudraCT方案编号：2015-001001-14。在线版本包含补充材料，可通过10.1186/s12967-022-03809-6获得。
Obesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment. Fasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC–QTOF-MS metabolomics, targeted LC–MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment. Participants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism. Our results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies. ClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14. The online version contains supplementary material available at 10.1186/s12967-022-03809-6.
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影响因子：
7.7
作者：
Floegel A;Stefan N;Yu Z;Mühlenbruch K;Drogan D;Joost HG;Fritsche A;Häring HU;Hrabě de Angelis M;Peters A;Roden M;Prehn C;Wang-Sattler R;Illig T;Schulze MB;Adamski J;Boeing H;Pischon T
通讯作者：
Pischon T
影响因子：
4.6
作者：
Bendinelli B;Vignoli A;Palli D;Assedi M;Ambrogetti D;Luchinat C;Caini S;Saieva C;Turano P;Masala G
通讯作者：
Masala G
影响因子：
6.1
作者：
Kwee LC;Ilkayeva O;Muehlbauer MJ;Bihlmeyer N;Wolfe B;Purnell JQ;Xavier Pi-Sunyer F;Chen H;Bahnson J;Newgard CB;Shah SH;Laferrère B
通讯作者：
Laferrère B
影响因子：
2.5
作者：
Carrillo, JA;Christensen, M;Bertilsson, L
通讯作者：
Bertilsson, L
影响因子：
3.4
作者：
Ayari, Imene;Fedeli, Ugo;Pavanello, Sofia
通讯作者：
Pavanello, Sofia