Mitochondrial topoisomerase I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity.
OBJECTIVE
Doxorubicin is one of the most effective chemotherapeutic agents. However, up to 30% of the patients treated with doxorubicin suffer from congestive heart failure. The mechanism of doxorubicin cardiotoxicity is likely multifactorial and most importantly, the genetic factors predisposing to doxorubicin cardiotoxicity are unknown. On the basis of the fact that mtDNA lesions and mitochondrial dysfunctions have been found in human hearts exposed to doxorubicin and that mitochondrial topoisomerase 1 (Top1mt) specifically controls mtDNA homeostasis, we hypothesized that Top1mt knockout (KO) mice might exhibit hypersensitivity to doxorubicin.


METHODS
Wild-type (WT) and KO Top1mt mice were treated once a week with 4 mg/kg doxorubicin for 8 weeks. Heart tissues were analyzed one week after the last treatment.


RESULTS
Genetic inactivation of Top1mt in mice accentuates mtDNA copy number loss and mtDNA damage in heart tissue following doxorubicin treatment. Top1mt KO mice also fail to maintain respiratory chain protein production and mitochondrial cristae ultrastructure organization. These mitochondrial defects result in decreased O2 consumption, increased reactive oxygen species production, and enhanced heart muscle damage in animals treated with doxorubicin. Accordingly, Top1mt KO mice die within 45 days after the last doxorubicin injection, whereas the WT mice survive.


CONCLUSIONS
Our results provide evidence that Top1mt, which is conserved across vertebrates, is critical for cardiac tolerance to doxorubicin and adaptive response to doxorubicin cardiotoxicity. They also suggest the potential of Top1mt single-nucleotide polymorphisms testing to investigate patient susceptibility to doxorubicin-induced cardiotoxicity.
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology;
Salim
S
Khiati
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology;
Ilaria
I
Dalla Rosa
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute;
Carole
C
Sourbier
Laboratory of Molecular Cardiology, National Heart, Lung, and Blood Institute, NIH; and.
Xuefei
X
Ma
Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland.
V Ashutosh
VA
Rao
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute;
Leonard M
LM
Neckers
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology;
Hongliang
H
Zhang
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology; pommier@nih.gov.
Yves
Y
Pommier
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D015153:Blotting, Western; D066126:Cardiotoxicity / Q000201:enzymology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D005455:Fluorescent Antibody Technique; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology*
D000903:Antibiotics, Antineoplastic; D004272:DNA, Mitochondrial; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I