Biology subjects

Siuzdak, G.

Publications and source records attributed to Siuzdak, G..

3 recordsLinked to original sources

bioRxiv2018

Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells

Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6 and used as a first-line treatment for patients with estrogen receptor positive breast cancer. It has been shown that patients have improved progression-free survival when treated in combination with fulvestrant, an estrogen receptor antagonist. However, the mechanisms for this survival advantage are not known. We sought to analyze metabolic and transcriptomic changes in MCF-7 adenocarcinoma breast cancer cells following single and combined treatments to determine if selective metabolic pathways are targeted during combination therapy. Our results showed that individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy's synergism in the cell model. This study highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.\n\nHighlights{circ} First study employing multi-omics to investigate combined therapy on breast cancer cells\n{circ}Fulvestrant attenuates the pentose phosphate pathway and coenzyme production\n{circ}Synergism of palbociclib and fulvestrant was confirmed in vitro\n{circ}Altered key pathways have been identified\n\n\neTOC BlurbJohnson et al. applied an innovative multi-omics approach to decipher metabolic pathways affected by single versus combination dosing of palbociclib and fulvestrant in estrogen receptor positive breast cancer. Key metabolites and genes were correlated within metabolic pathways and shown to be involved in the drugs' synergism.

biochemistry↗

bioRxiv2017

Dietary xenoestrogens significantly 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.

cancer biology↗

bioRxiv2017

Exposing the Exposome with Global Metabolomics andCognitive Computing

Concurrent exposure to a wide variety of xenobiotics and their combined toxic effects can play a pivotal role in health and disease, yet are largely unexplored. Investigating the totality of these exposures, i.e. the exposome, and their specific biological effects constitutes a new paradigm for environmental health but still lacks high-throughput, user-friendly technology. We demonstrate the utility of mass spectrometry-based global exposure metabolomics combined with tailored database queries and cognitive computing for comprehensive exposure assessment and the straightforward elucidation of biological effects. The METLIN Exposome database has been redesigned to help identify environmental toxicants, food contaminants and supplements, drugs, and antibiotics as well as their biotransformation products, through its expansion with over 700,000 chemical structures to now include more than 950,000 unique small molecules. More importantly, we demonstrate how the XCMS/METLIN platform now allows for the readout of the biological effect of a toxicant through metabolomic-derived pathway analysis and further, cognitive computing provides a means of assessing the role of a potential toxicant. The presented workflow addresses many of the outstanding methodological challenges current exposome research is facing and will serve to gain a deeper understanding of the impact of environmental exposures and combinatory toxic effects on human health.

epidemiology↗