Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin‐treated childhood acute lymphoblastic leukemia survivors

Abstract

BACKGROUND Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) disrupting genes encoding for polypeptides that make ATP. METHODS This cross-sectional study examined mtDNA copy numbers/cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute Childhood ALL protocols who had received doxorubicin alone (42%) or with dexrazoxane (58%), a cardioprotectant. Mitochondrial DNA copies per cell and OXPHOS enzyme activities of nicotinamide adenine dinucleotide (NADH) dehydrogenase (Complex I, CI) and cytochrome c oxidase (Complex IV, CIV) were measured by quantitative real time-polymerase chain reaction (qRT-PCR) immunoassay 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 was significantly higher than for those who also received dexrazoxane (medians, 1106.3 and 310.5; P=0.001). No significant differences were detected between groups for CI or CIV activities. CONCLUSIONS Doxorubicin-treated survivors had increased PBMC mtDNA copies/cell and concomitant use of dexrazoxane was associated with lower mtDNA copies/cell. Due to a possible compensatory increase in mtDNA copies/cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning.

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

“…Another approach is to examine peripheral blood mononuclear cells (PBMCs), in which the transcriptome in DOX‐exposed PBMCs is highly similar to that in treated cardiomyocytes (Todorova et al, 2012). Of particular relevance to the findings of the current study, it would be of interest to extend investigation of the role of Mfn2 after DOX treatment using patient‐derived PBMCs, since systemic mitochondrial pathologies have been shown to correlate in PBMCs and in cardiac tissues (Lipshultz et al, 2016). …”

Body Surface Area and Baseline Blood Pressure Predict Subclinical Anthracycline Cardiotoxicity in Women Treated for Early Breast Cancer

“…This effect, at least in part, explains the increasing prevalence of cardiac dysfunction and heart failure in survivors of childhood cancer over subsequent decades [2, 38, 40, 41]. The mechanisms underlying this phenomenon remain to be fully elucidated given the multiple toxic effects of anthracyclines, but mitochondrial dysfunction (DNA damage and impaired bioenergetics [42]) and possibly cellular senescence (including shortening of telomere length and loss of cardiac progenitor cells [43]) may play a role. Meanwhile, declines in cardiac function after chemotherapy may also occur as a result of “multiple hits”: exposure to subsequent insults, such as coronary ischaemia, hypertension and impaired glucose homeostasis, the prevalence of which is high in cancer survivors [5, 41, 44].…”

Prevention of cardiotoxicity among survivors of childhood cancer

“…Dexrazoxane maintained its cardioprotective effects supporting the hypothesis that its mechanism acts by preventing iron‐based doxorubicin‐mediated oxidative stress and establishing that its cardioprotective effects were not exclusively due to targeting of topoisomerase II‐beta. Doxorubicin targets mitochondria and dexrazoxane abrogates these effects . Mitochondrial transcription in energy metabolism and apoptosis genes were significantly altered by doxorubicin administration but these changes were attenuated by pretreatment with dexrazoxane .…”