Dietary xenoestrogens significantly alter cellular metabolism induced by palbociclib/letrozole combination cancer therapy

Recently, a novel combination therapy (palbociclib + letrozole) 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. Specifically, amino acids and central carbon metabolites were attenuated while higher abundances were observed for fatty acids and most nucleic acid related metabolites in the combined group. Interestingly, exposure to model xenoestrogens appeared to partially counteract these effects.