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Non-invasive measures of the response of individual patients to cancer therapeutics is an emerging strategy in precision medicine. Platelets offer a potential dynamic marker for metabolism and bioenergetic responses in individual patients since they have active glycolysis and mitochondrial oxidative phosphorylation and can be easily isolated from a small blood sample. We have recently shown how the bioenergetic-metabolite interactome can be defined in platelets isolated from human subjects by measuring metabolites and bioenergetics in the same sample. In the present study, we used a model system to assess test the hypothesis that this interactome is modified by xenobiotics using exposure to the anti-cancer drug doxorubicin (Dox) in individual donors. We found that unsupervised analysis of the metabolome showed clear differentiation between the control and Dox treated group. Dox treatment resulted in a concentration-dependent decrease in bioenergetic parameters with maximal respiration being most sensitive and this was associated with significant changes in over 166 features. A metabolome-wide association study of Dox was also conducted, and Dox was found to have associations with metabolites in the glycolytic and TCA cycle pathways. Lastly, network analysis showed the impact of Dox on the bioenergetic-metabolite interactome and revealed profound changes in the regulation of reserve capacity. Taken together, these data support the conclusion that platelets are a suitable platform to predict and monitor therapeutic efficacy as well as anticipate susceptibility to toxicity in the context of precision medicine.
Pubmed ID: 31546171
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Commercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
View all literature mentionsAmerican chemical, life science and biotechnology company owned by Merck KGaA. Merger of Sigma Chemical Company and Aldrich Chemical Company. Provides organic and inorganic chemicals, building blocks, reagents, advanced materials and stable isotopes for chemical synthesis, medicinal chemistry and materials science, antibiotics, buffers, carbohydrates, enzymes, forensic tools, hematology and histology, nucleotides, proteins, peptides, amino acids and their derivatives.
View all literature mentionsAdjusting batch effects in microarray expression data using Empirical Bayes methods.
View all literature mentionsIntegrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.
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