The carboxylic ionophore monensin inhibits active drug efflux and modulates in vitro resistance in daunorubicin resistant Ehrlich ascites tumor cells.
Acquired cellular resistance to anthracycline and vinca alkaloid drugs (pleiotropic resistance) is commonly associated with reduced drug accumulation, a phenomenon which is thought to be partly due to increased energy-dependent drug efflux. We have previously detected increased plasma membrane traffic to, and content of, the acid endosomal compartment in pleiotropic resistant Ehrlich ascites and P388 leukemia cells. This suggested that the endosome could be associated with the pleiotropic resistance phenotype by a mechanism of vesicular drug trapping and transport. The present study was undertaken in order to test the effects of the carboxylic ionophores monensin and nigericin, which are known to both disrupt intracellular vesicular traffic and to raise intravesicular pH, with relation to the pleiotropic resistance phenotype. Both monensin and nigericin increased daunorubicin (DNR) accumulation in daunorubicin resistant Ehrlich ascites tumor cells (EHR2/DNR+) in a dose-dependent manner. Further, monensin inhibited glucose induced DNR efflux from EHR2/DNR+ cells loaded with drug by energy deprivation. On the other hand, monensin had only negligible effect on DNR accumulation and efflux in wild-type Ehrlich ascites tumor cells (EHR2). In a clonogenic assay system, monensin reduced resistance to DNR in EHR2/DNR+, whereas only an additive effect was obtained in EHR2. However, both ionophores proved too toxic in in vivo experiments. These results, showing that drugs known to disrupt endosomal functions also inhibit the pleiotropic resistance phenotype, support the suggested link between the endosome and pleiotropic resistance.
Sehested
M
M
Department of Pathology, University of Copenhagen, Herlev Hospital, Denmark.
Skovsgaard
T
T
Roed
H
H
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003630:Daunorubicin / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects*; D006056:Golgi Apparatus / Q000187:drug effects / Q000648:ultrastructure; D051379:Mice; D008854:Microscopy, Electron; D008985:Monensin / Q000494:pharmacology*; D009550:Nigericin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D008985:Monensin; D009550:Nigericin; D003630:Daunorubicin