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Updated: Mar 27, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic
Steven E Lipshultz1,2, Lynn M Anderson3, Tracie L Miller4
1Wayne State University School of Medicine, Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan.
Background:
Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate.
Methods:
This cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively.
Results:
At a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity.
Conclusions:
Doxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning.
Insights
Childhood cancer survivors treated with doxorubicin show increased mitochondrial DNA (mtDNA) copies, a potential compensatory response. Dexrazoxane use was linked to lower mtDNA copies, but long-term cardiac effects remain a concern.
Area of Science:
- Cardiology
- Oncology
- Mitochondrial Biology
Background:
- Doxorubicin chemotherapy can impair cardiac function in childhood cancer survivors by disrupting mitochondrial energy production.
- This disruption involves doxorubicin's interaction with mitochondrial DNA (mtDNA), affecting genes crucial for adenosine triphosphate synthesis.
Purpose of the Study:
- To investigate the relationship between doxorubicin treatment, dexrazoxane use, and mitochondrial DNA (mtDNA) copy numbers and oxidative phosphorylation (OXPHOS) in childhood cancer survivors.
- To assess potential compensatory mechanisms in mitochondrial function following chemotherapy.
Main Methods:
- A cross-sectional study involving 64 childhood acute lymphoblastic leukemia (ALL) survivors treated with doxorubicin alone or with dexrazoxane.
- Measurement of mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) enzyme activity (complex I and IV) in peripheral blood mononuclear cells (PBMCs).
Main Results:
- Survivors receiving doxorubicin alone had significantly higher mtDNA copy numbers per cell compared to those who received dexrazoxane.
- No significant differences in the activity of OXPHOS enzymes (complex I and IV) were observed between the groups.
Conclusions:
- Doxorubicin treatment is associated with an increased number of PBMCs mtDNA copies per cell in survivors.
- Concomitant dexrazoxane use correlated with a lower mtDNA copy number, suggesting a potential protective effect.
- The increased mtDNA copy number may represent a compensatory response to mitochondrial dysfunction, raising concerns about long-term cardiac health sustainability.
