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

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Journal of Nuclear Cardiology Aims and scope

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.

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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

References

  1. Chen MH, Colan SD, Diller L. Cardiovascular disease: Cause of morbidity and mortality in adult survivors of childhood cancers. Circ Res. 2011;108:619–28.

    Article  CAS  Google Scholar 

  2. Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012;52:1213–25.

    Article  CAS  Google Scholar 

  3. Carvalho RA, Sousa RP, Cadete VJ, Lopaschuk GD, Palmeira CM, Bjork JA, et al. Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy. Toxicology. 2010;270:92–8.

    Article  CAS  Google Scholar 

  4. Bauckneht M, Ferrarazzo G, Fiz F, Morbelli S, Sarocchi M, Pastorino F, et al. Doxorubicin effect on myocardial metabolism as a pre-requisite for subsequent development of cardiac toxicity: A translational 18F-FDG PET/CT observation. J Nucl Med. 2017;58:1638–45.

    Article  CAS  Google Scholar 

  5. Bauckneht M, Morbelli S, Fiz F, Ferrarazzo G, Piva R, Nieri A, et al. A score-based approach to 18F-FDG PET images as a tool to describe metabolic predictors of myocardial doxorubicin susceptibility. Diagnostics (Basel). 2017;26:7.

    Google Scholar 

  6. Sarocchi M, Bauckneht M, Arboscello E, Capitanio S, Marini C, Morbelli S, et al. An increase in myocardial 18-fluorodeoxyglucose uptake is associated with left ventricular ejection fraction decline in Hodgkin lymphoma patients treated with anthracycline. J Transl Med. 2018;16:295.

    Article  CAS  Google Scholar 

  7. Gorla AK, Sood A, Prakash G, Parmar M, Mittal BR. Substantial increase in myocardial FDG uptake on interim PET/CT may be an early sign of adriamycin-induced cardiotoxicity. Clin Nucl Med. 2016;41:462–3.

    Article  Google Scholar 

  8. Marini C, Ravera S, Buschiazzo A, Bianchi G, Orengo AM, Bruno S, et al. Discovery of a novel glucose metabolism in cancer: the role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt. Sci Rep. 2016;6:25092.

    Article  CAS  Google Scholar 

  9. Clarke JL, Mason PJ. Murine hexose-6-phosphate dehydrogenase: a bifunctional enzyme with broad substrate specificity and 6-phosphogluconolactonase activity. Arch Biochem Biophys. 2003;415:229–34.

    Article  CAS  Google Scholar 

  10. Bublitz C, Steavenson S. The pentose phosphate pathway in the endoplasmic reticulum. J Biol Chem. 1988;263:12849–53.

    CAS  PubMed  Google Scholar 

  11. Tsachaki M, Mladenovic N, Štambergová H, Birk J, Odermatt A. Hexose-6-phosphate dehydrogenase controls cancer cell proliferation and migration through pleiotropic effects on the unfolded-protein response, calcium homeostasis, and redox balance. FASEB J 2018;8:fj201700870RR.

  12. Rogoff D, Black K, McMillan DR, White PC. Contribution of hexose-6-phosphate dehydrogenase to NADPH content and redox environment in the endoplasmic reticulum. Redox Rep. 2010;15:64–70.

    Article  CAS  Google Scholar 

  13. Cossu I, Bottoni G, Loi M, Emionite L, Bartolini A, Di Paolo D, et al. Neuroblastoma-targeted nanocarriers improve drug delivery and penetration, delay tumor growth and abrogate metastatic diffusion. Biomaterials. 2015;68:89–99.

    Article  CAS  Google Scholar 

  14. Ponzoni M, Curnis F, Brignole C, Bruno S, Guarnieri D, Sitia L, et al. Enhancement of tumour homing by chemotherapy-loaded nanoparticles. Small. 2018;14:e1802886.

    Article  Google Scholar 

  15. Buschiazzo A, Cossu V, Bauckneht M, Orengo A, Piccioli P, Emionite L, et al. Effect of starvation on brain glucose metabolism and 18F-2-fluoro-2-deoxyglucose uptake: an experimental in vivo and ex-vivo study. EJNMMI Res. 2018;8:44.

    Article  Google Scholar 

  16. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.

    Article  CAS  Google Scholar 

  17. Ravera S, Bartolucci M, Cuccarolo P, Litamè E, Illarcio M, Calzia D, et al. Oxidative stress in myelin sheath: The other face of the extramitochondrial oxidative phosphorylation ability. Free Radic Res. 2015;49:1156–64.

    Article  CAS  Google Scholar 

  18. Castellani P, Angelini G, Delfino L, Matucci A, Rubartelli A. The thiol redox state of lymphoid organs is modified by immunization: role of different immune cell populations. Eur J Immunol. 2008;38:2419–25.

    Article  CAS  Google Scholar 

  19. Vené R, Delfino L, Castellani P, Balza E, Bertolotti M, Sitia R, et al. Redox remodeling allows and controls B cell activation and differentiation. Antioxid Redox Signal. 2010;13:1145–55.

    Article  Google Scholar 

  20. Scussolini M, Bauckneht M, Cossu V, Bruno S, Orengo A, Piccioli P, et al. G6Pase location in the endoplasmic reticulum: Implications on compartmental analysis of FDG uptake in cancer cells. Sci Rep 2019 (in press).

  21. Rosner B. Fundamentals of Biostatistics. 7th ed. Boston: Brooks/Cole; 2011.

    Google Scholar 

  22. Paranka NS, Dorr RT. Effect of doxorubicin on glutathione and glutathione-dependent enzymes in cultured rat heart cells. Anticancer Res. 1994;14:2047–52.

    CAS  PubMed  Google Scholar 

  23. Li L, Pan Q, Han W, Liu Z, Li L, Hu X. Schisandrin B prevents doxorubicin-induced cardiotoxicity via enhancing glutathione redox cycling. Clin Cancer Res. 2007;13:6753–60.

    Article  CAS  Google Scholar 

  24. Hrelia S, Fiorentini D, Maraldi T, Angeloni C, Bordoni A, Biagi PL, et al. Doxorubicin induces early lipid peroxidation associated with changes in glucose transport in cultured cardiomyocytes. Biochim Biophys Acta. 2002;1567:150–6.

    Article  CAS  Google Scholar 

  25. Dhingra R, Margulets V, Chowdhury SR, Thliveris J, Jassal D, Fernyhough P, et al. Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling. Proc Natl Acad Sci USA. 2014;111:E5537–44.

    Article  CAS  Google Scholar 

  26. Herman EH, Lipshultz SE, Rifai N, Zhang J, Papoian T, Yu ZX, et al. Use of cardiac troponin T levels as an indicator of doxorubicin-induced cardiotoxicity. Cancer Res. 1998;58:195–7.

    CAS  PubMed  Google Scholar 

  27. Zhong M, Alonso CE, Taegtmeyer H, Kundu BK. Quantitative PET imaging detects early metabolic remodeling in a mouse model of pressure-overload left ventricular hypertrophy in vivo. J Nucl Med. 2013;54:609–15.

    Article  CAS  Google Scholar 

  28. Rahman A, Carmichael D, Harris M, Roh JK. Comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes. Cancer Res. 1986;46:2295–9.

    CAS  PubMed  Google Scholar 

  29. Dávila-Román VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, et al. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2002;40:271e7.

  30. Depre C, Vanoverschelde JL, Taegtmeyer H. Glucose for the heart. Circulation. 1999;99:578–88.

    Article  CAS  Google Scholar 

  31. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, et al. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: Theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem. 1977;28:897–916.

    Article  CAS  Google Scholar 

  32. Bøtker HE, Goodwin GW, Holden JE, Doenst T, Gjedde A, Taegtmeyer H. Myocardial glucose uptake measured with fluorodeoxyglucose: A proposed method to account for variable lumped constants. J Nucl Med. 1999;40:1186–96.

    PubMed  Google Scholar 

  33. Jung KH, Lee JH, Thien Quach CH, Paik JY, Oh H, Park JW, et al. Resveratrol suppressed cancer cell glucose uptake by targeting reactive oxygen species-mediated hypoxia-inducible factor-1α activation. J Nucl Med. 2013;54:2161–7.

    Article  CAS  Google Scholar 

  34. Chen L, Zhou Y, Tang X, Yang C, Tian Y, Xie R, et al. EGFR mutation decreases FDG uptake in non-small cell lung cancer via the NOX4/ROS/GLUT1 axis. Int J Oncol. 2019;54:370–80.

    PubMed  Google Scholar 

  35. Wang G, Li Y, Yang Z, Xu W, Yang Y, Tan X. ROS mediated EGFR/MEK/ERK/HIF-1α loop regulates glucose metabolism in pancreatic cancer. Biochem Biophys Res Commun. 2018;500:873–8.

    Article  CAS  Google Scholar 

  36. Sen S, Kundu BK, Wu HC, Hashmi SS, Guthrie P, Locke LW, et al. Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. J Am Heart Assoc. 2013;2:e004796.

    Article  Google Scholar 

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Disclosure

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

Author information

Authors and Affiliations

  1. Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Matteo Bauckneht MD, Vanessa Cossu MS, Anna Maria Orengo MS, Selene Capitanio MD, Nikola Yosifov MS, Silvia Morbelli MD, PhD & Gianmario Sambuceti MD

  2. Laboratory of Experimental Therapy in Oncology, Istituto Giannina Gaslini, Genoa, Italy

    Fabio Pastorino MS, PhD & Mirco Ponzoni MS

  3. Cell Biology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Patrizia Castellani MS, Patrizia Piccioli MS & Anna Rubartelli MD

  4. Animal Facility, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Laura Emionite MS

  5. Department of Experimental Medicine, University of Genoa, Genoa, Italy

    Silvia Bruno MS & Silvia Ravera MS, PhD

  6. Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy

    Edoardo Lazzarini MS, PhD & Pietro Ameri MD, PhD

  7. Department of Internal Medicine & Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy

    Edoardo Lazzarini MS, PhD & Pietro Ameri MD, PhD

  8. Nuclear Medicine, Department of Health Sciences (DISSAL), University of Genoa, Largo R. Benzi 10, 16132, Genoa, Italy

    Matteo Bauckneht MD, Silvia Morbelli MD, PhD, Gianmario Sambuceti MD & Cecilia Marini MD, PhD

  9. CNR Institute of Molecular Bioimaging and Physiology, Milan, Italy

    Cecilia Marini MD, PhD

Authors
  1. Matteo Bauckneht MD
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  2. Fabio Pastorino MS, PhD
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  7. Laura Emionite MS
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Correspondence to Matteo Bauckneht MD.

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Funding

This study was partially funded by the program “Ricerca Corrente” to AR and line “Guest-Cancer Interactions” by Compagnia di San Paolo (to CM, project ID Prot.: 2015.AAI4110.U4917), Italian Ministry of Heath (EuroNanoMed II-2015 to FP and “Cinque per mille” 2014 and 2015 to AR) and Italian Association for Cancer Research (AIRC grants IG 14231 and 18474 to MP; IG 15434 to AR) and by Telethon to PP.

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Bauckneht, M., Pastorino, F., Castellani, P. et al. Increased myocardial 18F-FDG uptake as a marker of Doxorubicin-induced oxidative stress. J. Nucl. Cardiol. 27, 2183–2194 (2020). https://doi.org/10.1007/s12350-019-01618-x

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  • DOI: https://doi.org/10.1007/s12350-019-01618-x

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