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

Abstract

HighlightsSynergism of combined palbociclib/letrozole chemotherapy was examined by global metabolomicsCombination therapy led to more pronounced effects on the MCF-7 metabolome than single agentsDietary phyto- and mycoestrogens significantly affected the metabolic and anti-oncogenic response of the drugsImplications of these bio-active chemicals on therapeutic success in breast cancer patients appear plausibleIn 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.SummaryRecently, 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.

Understanding emerging bioactive metabolites with putative roles in cancer biology

“…Others continue to emerge, whereby, for example, a recent untargeted mass spectrometry-based metabolomics study identified a form of 2-HG, 2-hydroxyglutarate-lactone, that exists in human cells for which the regulation and putative function apart from 2-HG is unknown (53). Although we do not summarize the vast number of diet-derived bioactive metabolites that also continue to emerge such as phytoestrogens (54). Furthermore, some endogenous metabolites act as riboswitches to influence gene expression (55).…”

Mass spectometry based untargeted metabolomics in food and health area

“…Whether they are free or commercial tools, the processing is mainly the same, although it may differ in how the steps are carried out, some of them working with in-house made algorithms. In the literature reviewed, the most employed tools were open-source software as XCMS (R package or Online) [17,18,75,76], MZmine [16,77] and MetAlign [78]; and commercial software as Mass Profiler Pro (Agilent Technologies Inc.) [79,80], Progenesis QI (Non Linear Dynamics, Waters) [15,25,72], MarkerLynx (Waters) [81,82], SIEVE [49,85,86].…”

“…The controlled trial study of fish oil supplementation during pregnancy, ended in the detection of several altered metabolic pathways significantly associated with a reduced risk of asthma by age 5 [124]. Likewise, the effects of diets supplements were assessed, as selenium impact on metabolic disorders [93] or the use of xenoestrogens in combination with cancer therapy [76].…”