title: Mitochondrial DNA damage by bleomycin induces AML cell death.
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.affiliation: Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Room 7-116, 610 University Ave, Toronto, ON, M5G 2M9, Canada.
authors.forename: ManTek
authors.initials: M
authors.lastname: Yeung
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.forename: Carine
authors.initials: C
authors.lastname: Nemr
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Samantha
authors.initials: S
authors.lastname: Hershenfeld
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.forename: Sanduni
authors.initials: S
authors.lastname: Liyanage
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Jeevan
authors.initials: J
authors.lastname: Augustine
authors.forename: Eric A
authors.initials: EA
authors.lastname: Lee
authors.forename: Paul A
authors.initials: PA
authors.lastname: Spagnuolo
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Catherine
authors.initials: C
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Danny V
authors.initials: DV
authors.lastname: Jeyaraju
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Rebecca
authors.initials: R
authors.lastname: Laposa
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D001761:Bleomycin / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects; D009368:Neoplasm Transplantation
chemical_list: D000903:Antibiotics, Antineoplastic; D004272:DNA, Mitochondrial; D001761:Bleomycin