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

• Published in: Cell chemical biology Vol. 25; no. 3; pp. 291 - 300.e3
• Main Authors: Warth, Benedikt, Raffeiner, Philipp, Granados, Ana, Huan, Tao, Fang, Mingliang, Forsberg, Erica M., Benton, H. Paul, Goetz, Laura, Johnson, Caroline H., Siuzdak, Gary
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 15.03.2018
• Subjects: bioactive food constituents; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Carbon - metabolism; CDK4/6 inhibitor; combinatory chemotherapy; Diet; drug-exposome interactions; endocrine-disrupting chemicals; Female; Genistein - chemistry; Genistein - pharmacology; Humans; Ibrance; Letrozole - chemistry; Letrozole - pharmacology; Letrozole - therapeutic use; MCF-7 Cells; metabolic pathway analysis; Metabolome - drug effects; Metabolomics; mTOR; Phytoestrogens - chemistry; Phytoestrogens - pharmacology; Piperazines - chemistry; Piperazines - pharmacology; Piperazines - therapeutic use; Principal Component Analysis; Pyridines - chemistry; Pyridines - pharmacology; Pyridines - therapeutic use; Receptors, Estrogen - metabolism; soy isoflavone; untargeted metabolomics; Zearalenone - chemistry; Zearalenone - pharmacology; drug-exposome interactions; untargeted metabolomics; bioactive food constituents; endocrine-disrupting chemicals; mTOR; metabolic pathway analysis; soy isoflavone; combinatory chemotherapy; Ibrance; CDK4/6 inhibitor
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2017.12.010

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. [Display omitted] •Synergism of palbociclib/letrozole chemotherapy was examined by metabolomics•Combination therapy led to more pronounced effects than the single agents•Dietary estrogens affected the metabolic and anti-oncogenic drug response•Implications of these bioactive chemicals on therapeutic success appear plausible Warth et al. used innovative global metabolomics and pathway prediction technology to describe the metabolic effects of the combined palbociclib/letrozole breast cancer therapy. Moreover, the role of dietary xenoestrogens on this treatment was examined by metabolite data, proliferation experiments, and functional assays.