It has been suggested that the inappropriate sequestration of weak-base chemotherapeutic drugs in acidic vesicles by multidrug-resistance (MDR) cells contributes to the mechanisms of drug resistance. The function of the acidic lysosomes can be altered in MDR cells, and so we investigated the effects of lysosomotropic agents on the secretion of lysosomal enzymes and on the intracellular distribution of the weak-base anthracycline daunomycin in drug-resistant renal proximal tubule PKSV-PRcol50 cells and their drug-sensitive PKSV-PR cell counterparts. Imaging studies using pH-dependent lysosomotropic dyes revealed that drug-sensitive and drug-resistant cells exhibited a similar acidic lysosomal pH (around 5.6—5.7), but that PKSV-PRcol50 cells contained more acidic lysosomes and secreted more of the lysosomal enzymes N-acetyl-β-hexosaminidase and β-glucuronidase than their parent PKSV-PR cells. Concanamycin A (CCM A), a potent inhibitor of the vacuolar H+-ATPase, but not the P-glycoprotein modulator verapamil, stimulated the secretion of N-acetyl-β-hexosaminidase in both drug-sensitive and drug-resistant cells. Fluorescent studies and Percoll density gradient fractionation studies revealed that daunomycin accumulated predominantly in the lysosomes of PKSV-PRcol50 cells, whereas in PKSV-PR cells the drug was distributed evenly throughout the nucleo-cytoplasmic compartments. CCM A did not impair the cellular efflux of daunomycin, but induced the rapid nucleo-cytoplasmic redistribution of the drug in PKSV-PRcol50 cells. In addition, CCM A and bafilomycin A1 almost completely restored the sensitivity of these drug-resistant cells to daunomycin, doxorubicin and epirubicin. These findings indicate that lysosomotropic agents that impair the acidic-pH-dependent accumulation of weak-base chemotherapeutic drugs may reverse anthracycline resistance in MDR cells with an expanded acidic lysosomal compartment.
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February 2003
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Research Article|
February 15 2003
Inhibitors of vacuolar H+-ATPase impair the preferential accumulation of daunomycin in lysosomes and reverse the resistance to anthracyclines in drug-resistant renal epithelial cells
Zahia OUAR;
Zahia OUAR
∗INSERM U478, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France
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Marcelle BENS;
Marcelle BENS
∗INSERM U478, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France
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Caroline VIGNES;
Caroline VIGNES
†IFR 02, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France
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Marc PAULAIS;
Marc PAULAIS
‡INSERM U426, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France,
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Claudine PRINGEL;
Claudine PRINGEL
§Laboratoire d'Histologie et Biologie Tumorale, Hôpital Tenon, 75020 Paris, France
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Jocelyne FLEURY;
Jocelyne FLEURY
§Laboratoire d'Histologie et Biologie Tumorale, Hôpital Tenon, 75020 Paris, France
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Françoise CLUZEAUD;
Françoise CLUZEAUD
∗INSERM U478, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France
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Roger LACAVE;
Roger LACAVE
§Laboratoire d'Histologie et Biologie Tumorale, Hôpital Tenon, 75020 Paris, France
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Alain VANDEWALLE
Alain VANDEWALLE
1
∗INSERM U478, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France
1To whom correspondence should be addressed (e-mail vandewal@bichat.inserm.fr).
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Publisher: Portland Press Ltd
Received:
September 06 2002
Revision Received:
October 21 2002
Accepted:
November 18 2002
Accepted Manuscript online:
November 18 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 370 (1): 185–193.
Article history
Received:
September 06 2002
Revision Received:
October 21 2002
Accepted:
November 18 2002
Accepted Manuscript online:
November 18 2002
Citation
Zahia OUAR, Marcelle BENS, Caroline VIGNES, Marc PAULAIS, Claudine PRINGEL, Jocelyne FLEURY, Françoise CLUZEAUD, Roger LACAVE, Alain VANDEWALLE; Inhibitors of vacuolar H+-ATPase impair the preferential accumulation of daunomycin in lysosomes and reverse the resistance to anthracyclines in drug-resistant renal epithelial cells. Biochem J 15 February 2003; 370 (1): 185–193. doi: https://doi.org/10.1042/bj20021411
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