Metabolomics reveals that dietary xenoestrogens alter cellular metabolism induced by palbociclib/letrozole combination cancer therapy

HighlightsO_LISynergism of combined palbociclib/letrozole chemotherapy was examined by global metabolomics\nC_LIO_LICombination therapy led to more pronounced effects on the MCF-7 metabolome than single agents\nC_LIO_LIDietary phyto- and mycoestrogens significantly affected the metabolic and anti-oncogenic response of the drugs\nC_LIO_LIImplications of these bio-active chemicals on therapeutic success in breast cancer patients appear plausible\nC_LI\n\nIn BriefWarth 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.\n\nSummaryRecently, the palbociclib/letrozole combination therapy was granted accelerated 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 on this treatment. 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 partially counteract these effects.