Alterations in the expression of cytochrome c oxidase subunits in doxorubicin-resistant leukemia K562 cells

Grandjean, Fabienne; Brémaud, Laure; Robert, Jacques; Ratinaud, Marie‐Hélène

doi:10.1016/s0006-2952(01)00865-6

Cited by 24 publications

(25 citation statements)

References 42 publications

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“…Several mitochondrial modifications due to chronic exposure to DOX have been previously reported (Denis-Gay et al, 1998;Campone et al, 2001;Childs et al, 2002;Grandjean et al, 2002). The clone studied in this work was characterized by a change of mitochondrial morphology, an increase in Complex I activity, an inhibition of PTP opening and a decrease in cytochrome c and CyD contents.…”

Section: Mitochondria In Dox-resistant Cells F De Oliveira Et Alsupporting

confidence: 55%

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

Oliveira

Chauvin

Ronot³

et al. 2005

Oncogene

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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 Ca 2 þ 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 CsAlike 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.

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Section: Mitochondria In Dox-resistant Cells F De Oliveira Et Alsupporting

confidence: 55%

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

Oliveira

Chauvin

Ronot³

et al. 2005

Oncogene

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“…32 We also cannot rule out mutations in nuclear genes necessary for myocardial function, mtDNA maintenance or mtDNA repair. 33 In a recently completed Phase I study with DOXO-EMCH, the albumin-binding prodrug showed a good safety profile and antitumor efficacy. 8 Forty-one patients with advanced cancer disease were treated with 2-6 intravenous cycles of DOXO-EMCH once every 3 weeks at a dose level of 20-340 mg/m 2 doxorubicin equivalents.…”

Section: Table III -Lack Of Mitochondrial Effects Of Doxorubicin and mentioning

confidence: 99%

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

Lebrecht

Geist

Ketelsen

et al. 2006

Intl Journal of Cancer

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Doxorubicin causes a chronic cardiomyopathy in which genetic and functional lesions of mitochondria accumulate in the longterm and explain in part the delayed onset of heart dysfunction. DOXO-EMCH a 6-maleimidocaproyl hydrazone derivative of doxorubicin, is an albumin binding prodrug which has entered clinical trials because of its superior antitumor and toxicological profile. In the present work, we examined the chronic cardiotoxicity of DOXO-EMCH in direct comparison with doxorubicin. Rats (11 weeks of age) were treated with intravenous doxorubicin (0.8 mg/kg weekly for 7 weeks), an equimolar dose of DOXO-EMCH (1.1 mg/kg), or with 3.3 mg/kg of DOXO-EMCH. Controls received saline. Animals were euthanized at 48th week. Rats exposed to doxorubicin had a severe clinical, and histopathological cardiomyopathy with depressed myocardial activity of cytochrome c-oxidase (COX, 26% of controls), reduced expression of the mtDNA-encoded COX II subunit, decreased mtDNA copy numbers (46% of controls), and high levels of malondialdehyde and superoxide (787% of controls). All parameters were highly correlated with myocardial damage. Both DOXO-EMCH groups did not differ from controls with regard to clinical symptomatology, mortality and mitochondrial enzymes, although the myocardia of the high-dose group had slightly increased histopathological abnormalities, depressed mtDNA copies (74% of controls) and elevated superoxide levels (347% of controls). Doxorubicin-exposed hearts and to a lesser extent the myocardia of both DOXO-EMCH groups contained mtDNA-deletions. In summary both DOXO-EMCH doses were superior over doxorubicin with respect to clinical and histopathological evidence of cardiomyopathy, myocardial COX-activity, COX II expression, mtDNA-content, mtDNA mutation loads and superoxide production in rats. ' 2006 Wiley-Liss, Inc.Key words: doxorubicin prodrug; mitochondria cytochrome oxidase; DNA mitochondrial; reactive oxygen species Doxorubicin is an antineoplastic anthracycline that is widely used in the treatment of leukemia and lymphoma, breast and ovarian carcinoma and many other solid tumors. Bone marrow suppression with maximum toxicity after 7-10 days and a rapid recovery thereafter generally limits the escalation of single doses. Cumulative doses of doxorubicin exceeding 500 mg/m 2 in contrast, are curtailed by a late-onset and irreversible cardiotoxicity. The antitumor potency and toxicological profile of anthracyclines has been the impetus for a diligent search for more effective and less toxic anthracycline analogues, and 2,000 derivatives have been developed during the past 20 years.2 Despite these efforts, daunorubicin, epirubicin, idarubicin, pirarubicin, zorubicin, aclarubicin and carminomycin have not satisfactorily improved the therapeutic index of anthracyclines in clinical practice. 3To improve the therapeutic potential of doxorubicin, we have developed a macromolecular prodrug in which doxorubicin is derivatized at its C-13 keto-position with a thiol-binding spacer molecule (i.e., 6-maleimidocaproyl ...

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“…After intravenous injection, the antibiotic quickly disappears from the plasma, which indicates a dynamic distribution of doxorubicin to the organs and tissues. Doxorubicin does not cross the blood-brain barrier and very slightly penetrates the placental barrier and gets into the mother's milk (Grandjean et al 2002). Doxorubicin is metabolised in the liver (inter alia to the form of active doxorubicinol) and it is excreted with the bile (up to 50%) and in small quantities in the urine (Nygren & Lundgren 1997).…”

Section: The Characteristics Of Selected Drugs Causing Multidrug Resimentioning

confidence: 99%

“…Resistance to doxorubicin occurs through multiple mechanisms, the best known of which is connected to the over-expression of Pgp (Grandjean et al 2002) (see below). Several modifications in mitochondrial oxido-reductase activity have been encountered in human K562 leukaemia cells resistant to doxorubicin.…”

Section: The Characteristics Of Selected Drugs Causing Multidrug Resimentioning

confidence: 99%

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Sawicka

Kalinowska

Skierski

et al. 2004

Journal of Pharmacy and Pharmacology

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It is assumed that proteins from the ABC family (i.e., glycoprotein P (Pgp)) and a multidrug resistance associated protein (MRP) play a main role in the occurrence of multidrug resistance (MDR) in tumour cells. Other factors that influence the rise of MDR are mechanisms connected with change in the effectiveness of the glutathione cycle and with decrease in expression of topoisomerases I and II. The aim of this review is to characterize drugs applied in anti-tumour therapy and to describe the present state of knowledge concerning the mechanisms of MDR occurrence, as well as the pharmacological agents applied in reducing this phenomenon.

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Alterations in the expression of cytochrome c oxidase subunits in doxorubicin-resistant leukemia K562 cells

Cited by 24 publications

References 42 publications

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

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

The 6‐maleimidocaproyl hydrazone derivative of doxorubicin (DOXO‐EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

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