A precision medicine approach to defining the impact of doxorubicin on the bioenergetic-metabolite interactome in human platelets

• Published in: Redox biology Vol. 28; p. 101311
• Main Authors: Smith, Matthew Ryan, Chacko, Balu K., Johnson, Michelle S., Benavides, Gloria A., Uppal, Karan, Go, Young-Mi, Jones, Dean P., Darley-Usmar, Victor M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2020; Elsevier
• Subjects: Blood Platelets - drug effects; Blood Platelets - metabolism; Case-Control Studies; Citric Acid Cycle - drug effects; Dose-Response Relationship, Drug; Doxorubicin - adverse effects; Energy Metabolism - drug effects; Glycolysis - drug effects; Humans; Metabolome - drug effects; Metabolomics - methods; Precision Medicine; Research Paper; Unsupervised Machine Learning
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2019.101311

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. [Display omitted] •Chemotherapeutic drug doxorubicin dose-dependently inhibited bioenergetic parameters in platelets.•Doxorubicin induced metabolite alterations in multiple pathways that modulate cellular bioenergetics.•The interactome revealed novel interactions between bioenergetic parameters and metabolites in platelets.•The integration of platelet bioenergetics with the metabolome can be utilized for precision medicine strategies.