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Effects of permeability transition inhibition and decrease in cytochrome c content on doxorubicin toxicity in K562 cells

Oncogene volume 25, pages 2646–2655 (2006)Cite this article

Abstract

As mitochondria play a key role in the commitment to cell death, we have investigated the mitochondrial consequences of resistance to doxorubicin (DOX) in K562 cells. We found that the permeability transition pore (PTP) inhibitor cyclosporine A (CsA) failed to inhibit PTP opening in the resistant clone. Moreover, the Ca2+ loading capacity in the resistant clone was identical to that observed in the parent cells in the presence of CsA, suggesting that the PTP was already inhibited in a CsA-like manner in the resistant cells. In agreement with this proposal, the mitochondrial target of CsA cyclophilin D (CyD) decreased by half in the resistant cells. The levels of adenine nucleotide translocator, voltage anion-dependent channel, Bax, Bcl-2, Bcl-xL, AIF and Smac/Diablo, were similar in both cell lines, whereas cytochrome c content was divided by three in the resistant cells. Since P-glycoprotein inhibition did not restore DOX toxicity in the resistant cells, while DOX-induced cell death in the parent cells was prevented by either PTP inhibition or siRNA-induced decrease in cytochrome c content, we conclude that the inhibition of PTP opening and the decrease in cytochrome c content participate in the mechanism that makes K562 cells resistant to DOX.

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Abbreviations

DOX:

doxorubicin

P-gp:

P-glycoprotein

ROS:

reactive oxygen species

PTP:

permeability transition pore

EGTA:

ethylene glycol-bis(β-aminoethyl ether) N,N,N′,N′-tetraacetic acid

MOPS:

4-morpholinepropanesulfonic acid

CsA:

cyclosporine A

CyD:

cyclophilin D

VDAC:

voltage anion-dependent channel

ANT:

adenine nucleotide translocator

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Acknowledgements

We thank Isabelle Pignot-Paintrand for expert assistance with electron microscopy, Claude Cochet, Odile Filhol-Cochet and Yan Burelle for helpful discussions and Dan Veale for correcting the manuscript. This work was supported by Grants from INSERM, the Ministère de l’Enseignement de la Recherche et de la Technologie (MERT), the Association pour la Recherche sur le Cancer, the Association Espoir, AGARO, GEFLUC (Dauphiné Savoie) and by an Aventis Fellowship (to FDO).

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Authors and Affiliations

  1. INSERM E-0221 Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier, Grenoble, France

    F De Oliveira, C Chauvin, X Leverve & E Fontaine

  2. Laboratoire de Dynamique Cellulaire, EPHE, UMR-CNRS, Institut Albert Bonniot, La Tronche, France

    X Ronot

  3. Département de cancérologie et d’hématologie, Hôpital Albert Michallon, Grenoble, France

    M Mousseau

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  1. F De Oliveira
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  2. C Chauvin
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  4. M Mousseau
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  5. X Leverve
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Correspondence to E Fontaine.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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De Oliveira, F., Chauvin, C., Ronot, X. et al. Effects of permeability transition inhibition and decrease in cytochrome c content on doxorubicin toxicity in K562 cells. Oncogene 25, 2646–2655 (2006). https://doi.org/10.1038/sj.onc.1209293

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