Journal
CELL CHEMICAL BIOLOGY
Volume 25, Issue 3, Pages 291-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2017.12.010
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Funding
- Austrian Science Fund (FWF) [J-3808]
- George E. Hewitt Foundation for Medical Research
- NIH [R01 GMH4368, PO1 A1043376-02S1]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM114368] Funding Source: NIH RePORTER
- Austrian Science Fund (FWF) [J 3808] Funding Source: researchfish
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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.
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