Data from 13 individual donors are shown for ( C) basal (basal OCR – AA OCR), ( D) ATP-linked (AL) (basal OCR – oligomycin OCR), ( E) maximal (FCCP OCR – AA OCR), ( F) reserve capacity (RC) (FCCP OCR – basal OCR) ( G) proton leak (PL) (oligomycin OCR – AA OCR), calculated and are expressed as mean ± SEM with each dot representing the average data from a single donor, n = 5–6 replicates for each parameter. Data is represented as the mean ± SEM for 5–6 technical replicates for this donor. ( B) The Dox concentration dependent inhibition of Basal, ATP linked, Maximal and Reserve Capacity. ( A) Platelets from a representative donor are shown with and without incubation with Doxorubicin (Dox) (0–25 μM) for 3 h after which a mitochondrial stress test was performed by first measuring basal OCR, followed by sequential injection of oligomycin (Oligo) (1 μg/ml), FCCP (0.6 μM), antimycin A (AntiA) (10 μM) and 2-deoxyglucose (50 mM). Published by Elsevier B.V.ĭoxorubicin inhibits mitochondrial respiration. 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.Ĭopyright © 2019. Lastly, network analysis showed the impact of Dox on the bioenergetic-metabolite interactome and revealed profound changes in the regulation of reserve capacity.
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.
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. We found that unsupervised analysis of the metabolome showed clear differentiation between the control and Dox treated group. 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 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. 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. Non-invasive measures of the response of individual patients to cancer therapeutics is an emerging strategy in precision medicine.
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