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Cell Chem Biol. 2018 Mar 15;25(3):291-300.e3. doi: 10.1016/j.chembiol.2017.12.010. Epub 2018 Jan 11.

Metabolomics Reveals that Dietary Xenoestrogens Alter Cellular Metabolism Induced by Palbociclib/Letrozole Combination Cancer Therapy.

Author information

1
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. Electronic address: benedikt.warth@univie.ac.at.
2
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
3
The Scripps Research Institute, Scripps Center for Metabolomics and Mass Spectrometry, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
4
Nanyang Technological University, School of Civil and Environmental Engineering, 50 Nanyang Avenue, Singapore 639798, Singapore.
5
Department of Surgery, Scripps Clinic Medical Group, La Jolla, CA 92037, USA.
6
Department of Environmental Health Sciences, Yale School of Public Health, Yale University, 60 College Street, New Haven, CT 06520, USA.
7
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. Electronic address: siuzdak@scripps.edu.

Abstract

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.

KEYWORDS:

CDK4/6 inhibitor; Ibrance; bioactive food constituents; combinatory chemotherapy; drug-exposome interactions; endocrine-disrupting chemicals; mTOR; metabolic pathway analysis; soy isoflavone; untargeted metabolomics

PMID:
29337187
PMCID:
PMC5856613
[Available on 2019-03-15]
DOI:
10.1016/j.chembiol.2017.12.010

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