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Cardiac molecular pathways influenced by doxorubicin treatment in mice

Bulten, B. F., Sollini, M., Boni, R., Massri, K., de Geus-Oei, L-F., van Laarhoven, H. W. M., Slart, R. H. J. A. & Erba, P. A., 21-Feb-2019, In : Scientific Reports. 9, 10 p., 2514.

Research output: Contribution to journalArticleAcademicpeer-review

  • Ben F. Bulten
  • Martina Sollini
  • Roberto Boni
  • Katrin Massri
  • Lioe-Fee de Geus-Oei
  • Hanneke W. M. van Laarhoven
  • Riemer H. J. A. Slart
  • Paola A. Erba

Doxorubicin (DOX) is a potent chemotherapeutic with distinct cardiotoxic properties. Understanding the underlying cardiotoxic mechanisms on a molecular level would enable the early detection of cardiotoxicity and implementation of prophylactic treatment. Our goal was to map the patterns of different radiopharmaceuticals as surrogate markers of specific metabolic pathways induced by chemotherapy. Therefore, cardiac distribution of Tc-99m-sestamibi, Tc-99m-Annexin V, Tc-99m-glucaric acid and [F-18]FDG and cardiac expression of Bcl-2, caspase-3 and -8, TUNEL, HIF-1 alpha, and p53 were assessed in response to DOX exposure in mice. A total of 80 mice (64 treated, 16 controls) were evaluated. All radiopharmaceuticals showed significantly increased uptake compared to controls, with peak cardiac uptake after one (Tc-99m-Annexin V), two (Tc-99m-sestamibi), three ([F-18]FDG), or four (Tc-99m-glucaric acid) cycles of DOX. Strong correlations (p <0.01) were observed between Tc-99m-Annexin V, caspase 3 and 8, and TUNEL, and between [F-18]FDG and HIF-1 alpha. This suggests that the cardiac DOX response starts with apoptosis at low exposure levels, as indicated by Tc-99m-Annexin V and histological apoptosis markers. Late process membrane disintegration can possibly be detected by Tc-99m-sestamibi and Tc-99m-glucaric acid. [F-18]FDG signifies an early adaptive response to DOX, which can be further exploited clinically in the near future.

Original languageEnglish
Article number2514
Number of pages10
JournalScientific Reports
Volume9
Publication statusPublished - 21-Feb-2019

    Keywords

  • EJECTION FRACTION, GLUCARIC ACID, CANCER, CARDIOTOXICITY, APOPTOSIS, IDENTIFICATION, DYSFUNCTION, KINETICS

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