1. ¹INSERM E-0221 Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier, Grenoble, France
2. ²Laboratoire de Dynamique Cellulaire, EPHE, UMR-CNRS, Institut Albert Bonniot, La Tronche, France
3. ³Département de cancérologie et d'hématologie, Hôpital Albert Michallon, Grenoble, France

Correspondence: Professor E Fontaine, Laboratoire de Bioénergétique Fondamentale et Appliquée, INSERM E-0221, Université Joseph Fourier – BP 53, F-38041 Grenoble Cedex, France. E-mail: eric.fontaine@ujf-grenoble.fr

Received 21 October 2004; Revised 18 October 2005; Accepted 4 November 2005; Published online 12 December 2005.

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-x_L, 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.