Skip to main content
SpringerLink
Log in

Mitochondrial DNA damage by bleomycin induces AML cell death

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465

    Article  CAS  PubMed  Google Scholar 

  2. Sawyer DE, Van Houten B (1999) Repair of DNA damage in mitochondria. Mutat Res 434:161–176

    Article  CAS  PubMed  Google Scholar 

  3. Wallace DC (2010) Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 51:440–450

    CAS  PubMed  Google Scholar 

  4. Weissman L, de Souza-Pinto NC, Stevnsner T, Bohr VA (2007) DNA repair, mitochondria, and neurodegeneration. Neuroscience 145:1318–1329

    Article  CAS  PubMed  Google Scholar 

  5. Skrtic M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z et al (2011) Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 20:674–688

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M et al (2013) BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12:329–341

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Chen J, Stubbe J (2005) Bleomycins: towards better therapeutics. Nat Rev Cancer 5:102–112

    Article  CAS  PubMed  Google Scholar 

  8. Froudarakis M, Hatzimichael E, Kyriazopoulou L, Lagos K, Pappas P, Tzakos AG et al (2013) Revisiting bleomycin from pathophysiology to safe clinical use. Crit Rev Oncol Hematol 87:90–100

    Article  PubMed  Google Scholar 

  9. Santos JH, Meyer JN, Mandavilli BS, Van Houten B (2006) Quantitative PCR-based measurement of nuclear and mitochondrial DNA damage and repair in mammalian cells. Methods Mol Biol 314:183–199

    Article  CAS  PubMed  Google Scholar 

  10. Bellarosa D, Ciucci A, Bullo A, Nardelli F, Manzini S, Maggi CA et al (2001) Apoptotic events in a human ovarian cancer cell line exposed to anthracyclines. J Pharmacol Exp Therapy 296:276–283

    CAS  Google Scholar 

  11. Xing J, Chen M, Wood CG, Lin J, Spitz MR, Ma J et al (2008) Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Natl Cancer Inst 100:1104–1112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Fonseca SB, Pereira MP, Mourtada R, Gronda M, Horton KL, Hurren R et al (2011) Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells. Chem Biol 18:445–453

    Article  CAS  PubMed  Google Scholar 

  13. Wisnovsky SP, Wilson JJ, Radford RJ, Pereira MP, Chan MR, Laposa RR et al (2013) Targeting mitochondrial DNA with a platinum-based anticancer agent. Chem Biol 20:1323–1328

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Brar SS, Meyer JN, Bortner CD, Van Houten B, Martin WJ 2nd (2012) Mitochondrial DNA-depleted A549 cells are resistant to bleomycin. Am J Physiol Lung Cell Mol Physiol 303:L413–L424

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Chamberlain GR, Tulumello DV, Kelley SO (2013) Targeted delivery of doxorubicin to mitochondria. ACS Chem Biol 8:1389–1395

    Article  CAS  PubMed  Google Scholar 

  16. Li M, Li Y, Yin Q, Mi R, Chen L, Du J et al (2014) Treatment with cyclophosphamide, vindesine, cytarabine, dexamethasone and bleomycin in patients with relapsed/refractory diffuse large B-cell lymphoma. Leuk Lymphoma 55:1578–1583

    Google Scholar 

  17. Tobias JS, Monson K, Gupta N, Macdougall H, Glaholm J, Hutchison I et al (2010) Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK head and neck (UKHAN1) trial. Lancet Oncol 11:66–74

    Article  PubMed  Google Scholar 

  18. Katsumata N, Yoshikawa H, Kobayashi H, Saito T, Kuzuya K, Nakanishi T et al (2013) Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102). Br J Cancer 108:1957–1963

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Aragona AM, Cuneo N, Soderini AH, Alcoba E, Greco A, Reyes C et al (2012) Tailoring the treatment of locally advanced squamous cell carcinoma of the vulva: neoadjuvant chemotherapy followed by radical surgery: results from a multicenter study. Int J Gynecol Cancer 22:1258–1263

    Article  PubMed  Google Scholar 

  20. Sikic BI (1986) Biochemical and cellular determinants of bleomycin cytotoxicity. Cancer Surv 5:81–91

    CAS  PubMed  Google Scholar 

  21. Cort A, Timur M, Ozdemir E, Kucuksayan E, Ozben T (2012) Synergistic anticancer activity of curcumin and bleomycin: an in vitro study using human malignant testicular germ cells. Mol Med Rep 5:1481–1486

    CAS  PubMed  Google Scholar 

  22. Sidik K, Smerdon MJ (1990) Bleomycin-induced DNA damage and repair in human cells permeabilized with lysophosphatidylcholine. Cancer Res 50:1613–1619

    CAS  PubMed  Google Scholar 

  23. Stivala LA, Prosperi E, Rossi R, Bianchi L (1993) Involvement of proliferating cell nuclear antigen in DNA repair after damage induced by genotoxic agents in human fibroblasts. Carcinogenesis 14:2569–2573

    Article  CAS  PubMed  Google Scholar 

  24. Muller C, Calsou P, Salles B (2000) The activity of the DNA-dependent protein kinase (DNA-PK) complex is determinant in the cellular response to nitrogen mustards. Biochimie 82:25–28

    Article  CAS  PubMed  Google Scholar 

  25. Sleijfer S (2001) Bleomycin-induced pneumonitis. Chest 120:617–624

    Article  CAS  PubMed  Google Scholar 

  26. Azambuja E, Fleck JF, Batista RG, Menna Barreto SS (2005) Bleomycin lung toxicity: who are the patients with increased risk? Pulm Pharmacol Ther 18:363–366

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Canadian Stem Cell Network and a Grant from the LLSC to PAS. We thank Jill Flewelling for administrative assistance and Bhozena Jhas for help in preparing the manuscript.

Conflict of interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Princess Margaret Cancer Centre, Ontario Cancer Institute, University Health Network, Room 7-116, 610 University Ave, Toronto, ON, M5G 2M9, Canada

    ManTek Yeung, Rose Hurren, Carine Nemr, Xiaoming Wang, Samantha Hershenfeld, Marcela Gronda, Sanduni Liyanage, Yan Wu, Jeevan Augustine, Danny V. Jeyaraju, Mark D. Minden & Aaron D. Schimmer

  2. School of Pharmacy, University of Waterloo, Kitchener, ON, Canada

    Eric A. Lee & Paul A. Spagnuolo

  3. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA

    Noel Southall, Catherine Chen & Wei Zheng

  4. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Rebecca Laposa

Authors
  1. ManTek Yeung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rose Hurren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carine Nemr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Samantha Hershenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marcela Gronda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sanduni Liyanage
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeevan Augustine
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eric A. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Paul A. Spagnuolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Noel Southall
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Catherine Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wei Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Danny V. Jeyaraju
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Mark D. Minden
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Rebecca Laposa
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Aaron D. Schimmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aaron D. Schimmer.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10495_2015_1119_MOESM1_ESM.ppt

Supplementary material 1 Figure 1: Histology of organs from mice treated with bleomycin: Heart, liver, kidney and lung organs were excised from mice treated with bleomycin (2.5mg/kg) as per Figure 4. Organs were sectioned and stained with hematoxylin and eosin. Representative sections from organs are shown of 1 section from 1 of 3 mice per group. Images were collected using a ScanScope XT microscope at 10X magnification. Scale bars are 100 µm. (PPT 3332 kb)

Supplementary material 2 (XLSX 12 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yeung, M., Hurren, R., Nemr, C. et al. Mitochondrial DNA damage by bleomycin induces AML cell death. Apoptosis 20, 811–820 (2015). https://doi.org/10.1007/s10495-015-1119-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-015-1119-z

Keywords

Search

Navigation