Cardiac molecular pathways influenced by doxorubicin treatment in mice

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

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Abstract

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 99m Tc-sestamibi, 99m Tc-Annexin V, 99m Tc-glucaric acid and [ 18 F]FDG and cardiac expression of Bcl-2, caspase-3 and -8, TUNEL, HIF-1α, 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 ( 99m Tc-Annexin V), two ( 99m Tc-sestamibi), three ([ 18 F]FDG), or four ( 99m Tc-glucaric acid) cycles of DOX. Strong correlations (p < 0.01) were observed between 99m Tc-Annexin V, caspase 3 and 8, and TUNEL, and between [ 18 F]FDG and HIF-1α. This suggests that the cardiac DOX response starts with apoptosis at low exposure levels, as indicated by 99m Tc-Annexin V and histological apoptosis markers. Late process membrane disintegration can possibly be detected by 99m Tc-sestamibi and 99m Tc-glucaric acid. [ 18 F]FDG signifies an early adaptive response to DOX, which can be further exploited clinically in the near future.

Original languageEnglish
Article number2514
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 21 Feb 2019

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Glucaric Acid
Doxorubicin
Radiopharmaceuticals
Caspase 8
In Situ Nick-End Labeling
Caspase 3
Apoptosis
Therapeutics
Metabolic Networks and Pathways
Biomarkers
Drug Therapy
Membranes
technetium Tc 99m annexin V

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Bulten, B. F., Sollini, M., Boni, R., Massri, K., de Geus-Oei, L. F., van Laarhoven, H. W. M., ... Erba, P. A. (2019). Cardiac molecular pathways influenced by doxorubicin treatment in mice. Scientific reports, 9(1), [2514]. https://doi.org/10.1038/s41598-019-38986-w
Bulten, Ben F. ; Sollini, Martina ; Boni, Roberto ; Massri, Katrin ; de Geus-Oei, Lioe Fee ; van Laarhoven, Hanneke W.M. ; Slart, Riemer H.J.A. ; Erba, Paola A. / Cardiac molecular pathways influenced by doxorubicin treatment in mice. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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abstract = "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 99m Tc-sestamibi, 99m Tc-Annexin V, 99m Tc-glucaric acid and [ 18 F]FDG and cardiac expression of Bcl-2, caspase-3 and -8, TUNEL, HIF-1α, 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 ( 99m Tc-Annexin V), two ( 99m Tc-sestamibi), three ([ 18 F]FDG), or four ( 99m Tc-glucaric acid) cycles of DOX. Strong correlations (p < 0.01) were observed between 99m Tc-Annexin V, caspase 3 and 8, and TUNEL, and between [ 18 F]FDG and HIF-1α. This suggests that the cardiac DOX response starts with apoptosis at low exposure levels, as indicated by 99m Tc-Annexin V and histological apoptosis markers. Late process membrane disintegration can possibly be detected by 99m Tc-sestamibi and 99m Tc-glucaric acid. [ 18 F]FDG signifies an early adaptive response to DOX, which can be further exploited clinically in the near future.",
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Cardiac molecular pathways influenced by doxorubicin treatment in mice. / Bulten, Ben F. (Corresponding Author); Sollini, Martina; Boni, Roberto; Massri, Katrin; de Geus-Oei, Lioe Fee; van Laarhoven, Hanneke W.M.; Slart, Riemer H.J.A.; Erba, Paola A.

In: Scientific reports, Vol. 9, No. 1, 2514, 21.02.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Sollini, Martina

AU - Boni, Roberto

AU - Massri, Katrin

AU - de Geus-Oei, Lioe Fee

AU - van Laarhoven, Hanneke W.M.

AU - Slart, Riemer H.J.A.

AU - Erba, Paola A.

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AB - 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 99m Tc-sestamibi, 99m Tc-Annexin V, 99m Tc-glucaric acid and [ 18 F]FDG and cardiac expression of Bcl-2, caspase-3 and -8, TUNEL, HIF-1α, 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 ( 99m Tc-Annexin V), two ( 99m Tc-sestamibi), three ([ 18 F]FDG), or four ( 99m Tc-glucaric acid) cycles of DOX. Strong correlations (p < 0.01) were observed between 99m Tc-Annexin V, caspase 3 and 8, and TUNEL, and between [ 18 F]FDG and HIF-1α. This suggests that the cardiac DOX response starts with apoptosis at low exposure levels, as indicated by 99m Tc-Annexin V and histological apoptosis markers. Late process membrane disintegration can possibly be detected by 99m Tc-sestamibi and 99m Tc-glucaric acid. [ 18 F]FDG signifies an early adaptive response to DOX, which can be further exploited clinically in the near future.

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