Abstract
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.
Highlights
The present study has focused on 3 aspects of the pleiotropically resistant cell viz (1) its capacity for recycling plasma membrane; (2) its endosomal compartment as defined by endosomal number, volume and membrane area; and (3) the influence on plasma membrane traffic by both the drug (DNR) to which the cell was made resistant, as well
We have previously reported that membrane traffic between the plasma membrane and the endosomal system was significantly increased in 4 pleiotropic resistant EHR cell lines compared to the sensitive EHR line (Sehested et al, 1987), and hypothesized that this phenomenon could offer an explanation of the increased active drug extrusion in resistant cells via drug trapping in the endosomal system and exocytosis therefrom to the extracellular medium
We have shown that verapamil, in a dose that nearly completely inhibits active DNR efflux in both DOX resistant P388 cells (Kessel & Wilberding, 1985), as well as in DNR resistant EHR cells (Friche et al.), significantly inhibits plasma membrane traffic in P388/DNR +
Summary
Wild-type P388 murine leukaemia cells (P388/S) were obtained from F.M. Shabel, Southern Research Institute, Birmingham, Alabama, and maintained as ascitic tumours in first-generation hybrids of female Swiss mice and male inbred DBA/2 mice by weekly transplantation of 107 cells per mouse. A DNR resistant P388 subline (P388/DNR+) was developed in vivo by treatment with increasing doses of DNR during weekly passages of the tumour. The resistant subline was maintained by i.p. treatment with a dose of DNR corresponding to LD10 as previously described (Dan0, 1971). DNR was omitted in the last passage before experiments
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