Daunorubicin efflux against a concentration gradient in non-P-glycoprotein multidrug-resistant lung-cancer cells
✍ Scribed by H. Sipko Mülder; Jan Lankelma; Henk Dekker; Henk J. Broxterman; Herbert M. Pinedo
- Publisher
- John Wiley and Sons
- Year
- 1994
- Tongue
- French
- Weight
- 948 KB
- Volume
- 59
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Multidrug-resistant, human non-small-cell lung carcinoma SW-I573/ZR120 (2RI2O) cells, not containing the drug efflux pump P-&coprotein (Pgp), have reduced initial daunorubicin (DN) accumulation rates and decreased cellular steady-state drug concentrations. Previously we found indications of the presence of a plasma membrane "vacuum cleaner", pumping DN directly from the membrane, and reported evidence of active DN pumping using digitonin. Further evidence of active DN pumping is now provided via a different methodology and the active drug pump flux is estimated. Cells were exposed to a flowing medium containing the cytotoxic agent DN. After reaching a steady state, in which net DN uptake equals net DN efflux, high concentration pulses o f vincristine (VCR) were injected into the Rowing medium. A rapid increase in cellular DN content was observed, while only a minimal effect was seen in SW-I573 wild-type cells. After passage of the VCR pulse, the extra accumulated DN was effluxed against a concentration gradient. Upon increasing the VCR concentration, a maximum pump inhibition was reached which was similar to the effect of cellular energy depletion. Similar effects were observed for Pgp-containing SW-I573/2R I60 (ZRI 60) cells as well as non-Pgp MDR human small-cell lung carcinoma GLC4/ADR cells.