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Updated: Aug 14, 2026
Preparation and Characterization of Lipophilic Doxorubicin Pro-drug Micelles
Published on: August 2, 2016
Effects of permeability transition inhibition and decrease in cytochrome c content on doxorubicin toxicity in K562
F De Oliveira1, C Chauvin, X Ronot
1INSERM E-0221 Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier, Grenoble, France.
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.
Insights
K562 cells resistant to doxorubicin (DOX) show inhibited mitochondrial permeability transition pore (PTP) opening and reduced cytochrome c release. These changes contribute to DOX resistance by preventing apoptosis.
Area of Science:
- Mitochondrial biology
- Cell death pathways
- Cancer chemotherapy resistance
Background:
- Mitochondria are crucial in regulating apoptosis.
- Doxorubicin (DOX) is a common chemotherapy drug that induces cell death.
- Understanding resistance mechanisms is vital for improving cancer treatment.
Purpose of the Study:
- Investigate mitochondrial changes associated with doxorubicin resistance in K562 cells.
- Determine the role of the permeability transition pore (PTP) and cytochrome c in DOX resistance.
Main Methods:
- Comparison of PTP opening, Ca2+ loading, and protein levels (cyclophilin D, cytochrome c) in DOX-sensitive and DOX-resistant K562 cells.
- Assessment of DOX-induced cell death inhibition by PTP inhibitors and siRNA targeting cytochrome c.
- Evaluation of P-glycoprotein's role in DOX resistance.
Main Results:
- DOX-resistant K562 cells exhibited inhibited PTP opening, independent of cyclosporine A (CsA).
- Cyclophilin D (CyD) levels were reduced by half in resistant cells, suggesting CsA-like PTP inhibition.
- Cytochrome c content was significantly decreased in resistant cells.
- P-glycoprotein inhibition did not restore DOX sensitivity.
Conclusions:
- Inhibition of PTP opening and reduced cytochrome c release are key mechanisms conferring DOX resistance in K562 cells.
- These mitochondrial alterations prevent DOX-induced apoptosis.
