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Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells

Oncogene volume 23, pages 7018–7030 (2004)Cite this article

Abstract

Doxorubicin is one of the most largely prescribed antitumor drug for the treatment of breast, liver and colon cancers as well as leukemia, but the cardiotoxicity of this anthracycline derivative limits its clinical use. Although doxorubicin is toxic to both cancer and cardiac cells, there are evidences suggesting that the mechanism of cell death is different for the two cell types. To investigate further this issue, we have compared the proapoptotic effects of doxorubicin and the functionally related anthracenedione compound mitoxantrone, which is also used in the clinic for the treatment of cancer. After evaluating the toxicity of the two drugs to mammary adenocarcinoma MTLn3 cells and H9C2 cardiomyocytes, we dissected the drug-induced apoptotic machinery by measuring the effects on the cell cycle progression, DNA condensation and fragmentation, production of endogenous peroxides and caspase activation. Both doxorubicin and mitoxantrone are potent inducers of apoptosis in H9C2 cardiomyocytes and MTLn3 breast cancer cells, but there are significant differences between the two cell types in terms of kinetics and order of the events. In particular, flow cytometry measurements of drug-induced changes in mitochondrial transmembrane potential and mitochondrial mass with different fluorescent probes suggested that the two drugs induced a progressive increase in mitochondrial mass in the cancer cells but not in the cardiac cells. The hypothesis was validated by means of electron microscopy, which revealed a significant increase in the number of mitochondria in drug-treated MTLn3 but not in H9C2 cells. The mitochondrial proliferation precedes the nuclear apoptosis in doxorubicin-treated MTLn3 cells. The changes in the architecture and number of mitochondria are linked to the drug-induced perturbation of the cell cycle progression and apoptosis. The proliferation of mitochondria could explain the higher toxicity of doxorubicin to cancer cells compared to cardiac cells and this suggests novel therapeutic opportunities to better control the cardiotoxicity of anthracyclines.

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Abbreviations

DOXO:

doxorubicin

FCS:

ftal calf serum

MFI:

mean of fluorescence intensity

MITO:

mitoxantrone

PBS:

phosphate-buffered saline

ROS:

reactive oxygen species

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Acknowledgements

This study was supported by research grants (to CB and PM) from the Ligue Nationale Contre le Cancer (Comité du Nord). We thank Pr R Nevière (EA 2689) and R Mazinghien (INSERM U524) for technical advice.

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Authors and Affiliations

  1. INSERM U-524 and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, Lille, 59045, France

    Jérôme Kluza & Christian Bailly

  2. INSERM U-459, Faculté de Médecine, Place de Verdun, Lille, 59045, France

    Philippe Marchetti & Miguel-Angel Gallego

  3. EA2689 Faculté de Médecine, Place de Verdun, Lille, 59045, France

    Steve Lancel

  4. Département de biostatistique, Centre Oscar Lambret, 3 Rue F Combemale, Lille, 59020, France

    Charles Fournier

  5. INSERM U-422 and service d'imagerie de l'université de Lille II, Place de Verdun, Lille, 59045, France

    Anne Loyens & Jean-Claude Beauvillain

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  1. Jérôme Kluza
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Correspondence to Christian Bailly.

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Kluza, J., Marchetti, P., Gallego, MA. et al. Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells. Oncogene 23, 7018–7030 (2004). https://doi.org/10.1038/sj.onc.1207936

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