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Lysosomotropic agents increase vinblastine efflux from mouse MDR proximal kidney cells exhibiting vectorial drug transport
Author(s) -
Lacave Roger,
Ouar Zahia,
Paulais Marc,
Bens Marcelle,
Ricci Sylvie,
Cluzeaud Francoise,
Vandewalle Alain
Publication year - 1999
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199902)178:2<247::aid-jcp14>3.0.co;2-k
Subject(s) - efflux , vinblastine , verapamil , intracellular , cytoplasm , biology , chemistry , pharmacology , microbiology and biotechnology , biochemistry , chemotherapy , calcium , genetics , organic chemistry
Vinblastine (VBL) transport and efflux were studied in mouse proximal tubule PKSV‐PR cells and in their multidrug‐resistant derivatives PKSV‐PR col50 cells. The PKSV‐PR col50 cells produced more mdr1b transcripts and had higher resistance to various drugs. PKSV‐PR col50 cells had a predominantly basal‐to‐apical flux of [ 3 H]VBL, 2.7 times larger than that in PKSV‐PR cells. This flux was partially inhibited by verapamil (VRP) (10 μM) and cyclosporin A (CsA) (200 nM). [ 3 H]VBL efflux was also greater in PKSV‐PR col50 than in PKSV‐PR cells. Treatment with NH 4 Cl (30 mM), a lysosomotropic weak base, and concanamycin A (CCM A) (20 nM), an inhibitor of the vacuolar H + /ATPase, further increased [ 3 H]VBL efflux from PKSV‐PR col50 cells. The cytoplasmic pH (pH cyt ) of these drug‐resistant cells transiently increased in the presence of NH 4 Cl (ΔpH cyt : +0.4). CCM A caused a moderate, delayed increase in pH cyt (ΔpH cyt : +0.1) and made the acidic intralysosomal compartment more alkaline (ΔpH lys : +1.3). VRP and CsA prevented the NH 4 Cl‐ and CCM A–induced [ 3 H]VBL efflux from PKSV‐PR col50 cells. However, VRP (10 μM) did not significantly affect pH cyt of PKSV‐PR col50 cells, the NH 4 Cl‐ and CCM A–induced pH cyt responses, and the effect of CCMA on pH lys . Thus, lysosomotropic agents may affect the kinetics of [ 3 H]VBL efflux. Our results also suggest that the inhibitory action of VRP on VBL efflux was not directly mediated by a pH‐dependent process in these drug‐resistant renal proximal tubule cells. J Cell Physiol 178:247–257, 1999. © 1999 Wiley‐Liss, Inc.