Increased plasma membrane traffic in daunorubicin resistant P388 leukaemic cells. Effect of daunorubicin and verapamil.
Numerous studies have indicated that the plasma membrane plays an important role in the development of resistance to anthracycline and vinca alkaloid drugs (pleiotropic resistance). We have previously shown that pleiotropically resistant Ehrlich ascites tumour cells, which are of epithelial origin, have a significantly increased plasma membrane traffic (endo/exocytosis) to the endosomal compartment compared to sensitive cells. The present study, using the same ultrastructural morphometric technique, has demonstrated a similar significant difference in plasma membrane traffic between daunorubicin resistant and sensitive P388 cell lines (which are of lymphoid origin). Furthermore, we have shown that this difference between the P388 sublines is accompanied by an approximately 4 fold increase in the plasma membrane area participating in recycling together with an increased endosomal volume, number and membrane area in resistant cells. Plasma membrane traffic in resistant cells was significantly inhibited by the calcium channel blocker verapamil, a well known modulator of anthracycline resistance, but unaffected by daunorubicin itself. The confirmation of this phenotype in an additional pleiotropically resistant cell type with a different histogenesis further supports a hypothesis of endosomal drug trapping and vesicular extrusion as a possible resistance mechanism.
Institute of Pathological Anatomy, University of Copenhagen, Herlev Hospital, Denmark.
M
M
Sehested
T
T
Skovsgaard
B
B
van Deurs
H
H
Winther-Nielsen
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects*; D003630:Daunorubicin / Q000627:therapeutic use*; D004351:Drug Resistance; D004705:Endocytosis; D005089:Exocytosis; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy* / Q000473:pathology; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure; D014700:Verapamil / Q000627:therapeutic use*
D014700:Verapamil; D003630:Daunorubicin