Increased myocardial 18 F-FDG uptake as a marker of Doxorubicin-induced oxidative stress

Matteo Bauckneht, Fabio Pastorino, Patrizia Castellani, Vanessa Cossu, Anna Maria Orengo, Patrizia Piccioli, Laura Emionite, Selene Capitanio, Nikola Yosifov, Silvia Bruno, Edoardo Lazzarini, Mirco Ponzoni, Pietro Ameri, Anna Rubartelli, Silvia Ravera, Silvia Morbelli, Gianmario Sambuceti, Cecilia Marini

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Abstract

Background: Oxidative stress and its interference on myocardial metabolism play a major role in Doxorubicin (DXR) cardiotoxic cascade. Methods: Mice models of neuroblastoma (NB) were treated with 5 mg DXR/kg, either free (Free-DXR) or encapsulated in untargeted (SL[DXR]) or in NB-targeting Stealth Liposomes (pep-SL[DXR] and TP-pep-SL[DXR]). Control mice received saline. FDG-PET was performed at baseline (PET1) and 7 days after therapy (PET2). At PET2 Troponin-I and NT-proBNP were assessed. Explanted hearts underwent biochemical, histological, and immunohistochemical analyses. Finally, FDG uptake and glucose consumption were simultaneously measured in cultured H9c2 in the presence/absence of Free-DXR (1 μM). Results: Free-DXR significantly enhanced the myocardial oxidative stress. Myocardial-SUV remained relatively stable in controls and mice treated with liposomal formulations, while it significantly increased at PET2 with respect to baseline in Free-DXR. At this timepoint, myocardial-SUV was directly correlated with both myocardial redox stress and hexose-6-phosphate-dehydrogenase (H6PD) enzymatic activity, which selectively sustain cellular anti-oxidant mechanisms. Intriguingly, in vitro, Free-DXR selectively increased FDG extraction fraction without altering the corresponding value for glucose. Conclusion: The direct correlation between cardiac FDG uptake and oxidative stress indexes supports the potential role of FDG-PET as an early biomarker of DXR oxidative damage.

Original languageEnglish
JournalJournal of Nuclear Cardiology
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • cardiotoxicity
  • Doxorubicin
  • myocardial metabolism
  • oxidative stress, hexose-6-phosphate-dehydrogenase
  • Positron emission tomography

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine

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