Increased myocardial 18F-FDG uptake as a marker of Doxorubicin-induced oxidative stress
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Oxidative stress and its interference on myocardial metabolism play a major role in Doxorubicin (DXR) cardiotoxic cascade.
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).
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.
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.
KeywordsPositron emission tomography cardiotoxicity Doxorubicin myocardial metabolism oxidative stress, hexose-6-phosphate-dehydrogenase
Doxorubicin-loaded stealth liposome (Caelyx)
YSHSHSYWLRSGGGC peptide-targeted, Doxorubicin-loaded stealth liposome
CRALKYSHSHSYWLRSGGG peptide-targeted, Doxorubicin-loaded stealth liposome
Reactive oxygen species
The authors have indicated that they have no financial conflict of interest.
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