Mitochondrial DNA damage by bleomycin induces AML cell death.

Therapeutic Approaches

Abstract

Mitochondria contain multiple copies of their own 16.6 kb circular genome. To explore the impact of mitochondrial DNA (mtDNA) damage on mitochondrial (mt) function and viability of AML cells, we screened a panel of DNA damaging chemotherapeutic agents to identify drugs that could damage mtDNA. We identified bleomycin as an agent that damaged mtDNA in AML cells at concentrations that induced cell death. Bleomycin also induced mtDNA damage in primary AML samples. Consistent with the observed mtDNA damage, bleomycin reduced mt mass and basal oxygen consumption in AML cells. We also demonstrated that the observed mtDNA damage was functionally important for bleomycin-induced cell death. Finally, bleomycin delayed tumor growth in xenograft mouse models of AML and anti-leukemic concentrations of the drug induced mtDNA damage in AML cells preferentially over normal lung tissue. Taken together, mtDNA-targeted therapy may be an effective strategy to target AML cells and bleomycin could be useful in the treatment of this disease.

Authors

Yeung, ManTek; Hurren, Rose; Nemr, Carine; Wang, Xiaoming; Hershenfeld, Samantha; Gronda, Marcela; Liyanage, Sanduni; Wu, Yan; Augustine, Jeevan; Lee, Eric A; Spagnuolo, Paul A; Southall, Noel; Chen, Catherine; Zheng, Wei; Jeyaraju, Danny V; Minden, Mark D; Laposa, Rebecca; Schimmer, Aaron D;

Keywords

  • Animals
  • Antibiotics, Antineoplastic/ pharmacology
  • Antibiotics, Antineoplastic/ therapeutic use
  • Bleomycin/ pharmacology
  • Bleomycin/ therapeutic use
  • Cell Death/ drug effects
  • Cell Line, Tumor
  • Cell Proliferation/ drug effects
  • DNA Damage/ drug effects
  • DNA, Mitochondrial/ metabolism
  • Heterografts
  • Humans
  • Leukemia, Myeloid, Acute/ drug therapy
  • Leukemia, Myeloid, Acute/ metabolism
  • Mice, SCID
  • Mitochondria/ drug effects
  • Neoplasm Transplantation

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