Metabolomics Reveals that Dietary Xenoestrogens Alter Cellular Metabolism Induced by Palbociclib/Letrozole Combination Cancer Therapy,Cell Chemical Biology

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Metabolomics Reveals that Dietary Xenoestrogens Alter Cellular Metabolism Induced by Palbociclib/Letrozole Combination Cancer Therapy
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-01-11 , DOI: 10.1016/j.chembiol.2017.12.010
Benedikt Warth ₁ , Philipp Raffeiner ₂ , Ana Granados ₃ , Tao Huan ₃ , Mingliang Fang ₄ , Erica M Forsberg ₃ , H Paul Benton ₃ , Laura Goetz ₅ , Caroline H Johnson ₆ , Gary Siuzdak ₇

Affiliation

The Scripps Research Institute, Scripps Center for Metabolomics and Mass Spectrometry, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; University of Vienna, Faculty of Chemistry, Department of Food Chemistry and Toxicology, Währingerstraße 38, 1090 Vienna, Austria; Vienna Metabolomics Center (VIME), University of Vienna, 1090 Vienna, Austria.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
The Scripps Research Institute, Scripps Center for Metabolomics and Mass Spectrometry, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Nanyang Technological University, School of Civil and Environmental Engineering, 50 Nanyang Avenue, Singapore 639798, Singapore.
Department of Surgery, Scripps Clinic Medical Group, La Jolla, CA 92037, USA.
Department of Environmental Health Sciences, Yale School of Public Health, Yale University, 60 College Street, New Haven, CT 06520, USA.
The Scripps Research Institute, Scripps Center for Metabolomics and Mass Spectrometry, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; The Scripps Research Institute, Department of Integrative and Computational Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Recently, the palbociclib/letrozole combination therapy was granted accelerated US FDA approval for the treatment of estrogen receptor (ER)-positive breast cancer. Since the underlying metabolic effects of these drugs are yet unknown, we investigated their synergism at the metabolome level in MCF-7 cells. As xenoestrogens interact with the ER, we additionally aimed at deciphering the impact of the phytoestrogen genistein and the estrogenic mycotoxin zearalenone. A global metabolomics approach was applied to unravel metabolite and pathway modifications. The results clearly showed that the combined effects of palbociclib and letrozole on cellular metabolism were far more pronounced than that of each agent alone and potently influenced by xenoestrogens. This behavior was confirmed in proliferation experiments and functional assays. Specifically, amino acids and central carbon metabolites were attenuated, while higher abundances were observed for fatty acids and most nucleic acid-related metabolites. Interestingly, exposure to model xenoestrogens appeared to counteract these effects.

中文翻译：

代谢组学揭示膳食异雌激素改变 Palbociclib/来曲唑组合癌症治疗诱导的细胞代谢

最近，哌柏西利/来曲唑联合疗法获得美国 FDA 加速批准，用于治疗雌激素受体（ER）阳性乳腺癌。由于这些药物的潜在代谢作用尚不清楚，我们在 MCF-7 细胞中研究了它们在代谢组水平上的协同作用。由于异种雌激素与内质网相互作用，我们还致力于破译植物雌激素金雀异黄酮和雌激素霉菌毒素玉米赤霉烯酮的影响。应用全局代谢组学方法来阐明代谢物和途径修饰。结果清楚地表明，哌柏西利和来曲唑对细胞代谢的联合影响比单独使用每种药物的影响要显着得多，并且受到异雌激素的强烈影响。这种行为在增殖实验和功能测定中得到证实。具体而言，氨基酸和中心碳代谢物减弱，而脂肪酸和大多数核酸相关代谢物的丰度较高。有趣的是，接触模型异雌激素似乎可以抵消这些影响。

更新日期：2018-03-16

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