Atypical multi-drug resistance (MDR): low sensitivity of a P-glycoprotein-expressing human T lymphoblastoid MDR cell line to classical P-glycoprotein-directed resistance-modulating agents

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Verapamil, cyclosporin A (CsA), the cyclosporin derivative SDZ PSC 833 and the novel cyclopeptolide SDZ 280–446 were tested for their capacity to chemosensitize a P-glycoprotein (Pgp)-expressing multi-drug resistant (MDR) variant of the CEM human T lymphoblastoid cell subline (CCRF ACTD 400 +). That MDR-CEM cell subline had been previously selected for MDR by actinomycin D and displayed a very high resistance phenotype: 3700-fold for actinomycin D, 3900-fold for vincristine, 1200-fold for taxol, 1000-fold for daunomycin (DAU) and 400-fold for colchicine. Interestingly, these MDR-CEM cells displayed little chemosensitization by resistance-modulating agents (RMA) which presumably work by inhibiting Pgp function. These MDR-CEM cells displayed virtually no chemosensitization by 1 μM verapamil or 1 μg/ml (about 0.8 μM) CsA, whereas their chemosensitization for different anticancer drugs (ACD) was rather stable (from 51− to 82-fold) with 1 μg/ml (about 0.8 μM) SDZ 280–446, while being very unbalanced (from 5− to 38-fold) with 1 μg/ml (about 0.8 μM) SDZ PSC 833. Exposure of the MDR-CEM cells to Pgp-directed RMAs, during their loading with DAU (DAU-loading phase), hardly restored DAU retention: SDZ 280–446 being as poorly active as SDZ PSC 833, and about only 3− and 4-fold more active than CsA and verapamil. In contrast, SDZ PSC 833 treatment of human MDR-KB and MDR-LoVo cell lines under the same conditions could restore most or all the DAU retention shown by the parental (Par) cells, in spite of their high level of resistance. By keeping the MDR-CEM cells in the presence of RMA throughout the experiment (both DAU-loading and DAU-efflux phases), a better DAU retention could be restored by the different RMAs used, their order of relative restoration activity being SDZ 280–446 3− to 4− fold > SDZ PSC 833 3− to 10-fold > CsA 2− to 4-fold > verapamil. Nevertheless, the level of DAU retention restored in the MDR-CEM cells reached a plateau at 50% of the Par-CEM cell level. Therefore, although the MDR-CEM cells expressed easily detectable membranous Pgp molecules and probably used them for DAU efflux, they displayed an additional efflux mechanism that was not sensitive to the Pgp inhibitors.

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