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

  • Matteo BaucknehtEmail author
  • 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
Original Article
  • 14 Downloads

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.

Keywords

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

Abbreviations

DXR

Doxorubicin

Free-DXR

Free Doxorubicin

SL[DXR]

Doxorubicin-loaded stealth liposome (Caelyx)

pep-SL[DXR]

YSHSHSYWLRSGGGC peptide-targeted, Doxorubicin-loaded stealth liposome

TP-pep-SL[DXR]

CRALKYSHSHSYWLRSGGG peptide-targeted, Doxorubicin-loaded stealth liposome

H6PD

Hexose-6-phosphate-dehydrogenase

HK

Hexokinase

PFK

Phosphofructokinase

G6PD

Glucose-6-phosphate-dehydrogenase

G6Pase

Glucose-6-phosphate-phosphatase

GR

Glutathione reductase

MDA

Malondialdehyde

GSH

Reduced glutathione

ROS

Reactive oxygen species

H2DCFDA

2′,7′-Dichlorofluorescein diacetate

Trx

Thioredoxin

Notes

Disclosure

The authors have indicated that they have no financial conflict of interest.

Supplementary material

12350_2019_1618_MOESM1_ESM.pptx (192 kb)
Supplementary material 1 (PPTX 192 kb)
12350_2019_1618_MOESM2_ESM.docx (21 kb)
Supplementary material 2 (DOCX 21 kb)
12350_2019_1618_MOESM3_ESM.pptx (2.1 mb)
Supplementary material 3 (PPTX 2126 kb)

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Copyright information

© American Society of Nuclear Cardiology 2019

Authors and Affiliations

  • Matteo Bauckneht
    • 1
    • 8
    Email author
  • Fabio Pastorino
    • 2
  • Patrizia Castellani
    • 3
  • Vanessa Cossu
    • 1
  • Anna Maria Orengo
    • 1
  • Patrizia Piccioli
    • 3
  • Laura Emionite
    • 4
  • Selene Capitanio
    • 1
  • Nikola Yosifov
    • 1
  • Silvia Bruno
    • 5
  • Edoardo Lazzarini
    • 6
    • 7
  • Mirco Ponzoni
    • 2
  • Pietro Ameri
    • 6
    • 7
  • Anna Rubartelli
    • 3
  • Silvia Ravera
    • 5
  • Silvia Morbelli
    • 1
    • 8
  • Gianmario Sambuceti
    • 1
    • 8
  • Cecilia Marini
    • 8
    • 9
  1. 1.Nuclear MedicineIRCCS Ospedale Policlinico San MartinoGenoaItaly
  2. 2.Laboratory of Experimental Therapy in OncologyIstituto Giannina GasliniGenoaItaly
  3. 3.Cell Biology UnitIRCCS Ospedale Policlinico San MartinoGenoaItaly
  4. 4.Animal FacilityIRCCS Ospedale Policlinico San MartinoGenoaItaly
  5. 5.Department of Experimental MedicineUniversity of GenoaGenoaItaly
  6. 6.Cardiovascular Disease UnitIRCCS Ospedale Policlinico San MartinoGenovaItaly
  7. 7.Department of Internal Medicine & Centre of Excellence for Biomedical ResearchUniversity of GenoaGenoaItaly
  8. 8.Nuclear Medicine, Department of Health Sciences (DISSAL)University of GenoaGenoaItaly
  9. 9.CNR Institute of Molecular Bioimaging and PhysiologyMilanItaly

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