In vitro efficacy of known P-glycoprotein modulators compared to droloxifene E and Z: Studies on a human T-cell leukemia cell line and their resistant variants

Volkmar Nüssler*, Renate Pelka-Fleisc, Frank Gieseler, Max Hasmann, Rainer Löser, Edith Gullis, Oliver Stötzer, Heinz Zwierzina, Wolfgang Wilmanns

*Corresponding author for this work
6 Citations (Scopus)

Abstract

P-glycoprotein (P-gp)-related resistance is one of the major obstacles in treating leukemia patients. Therefore, it is of clinical interest to find new potential modulators and compare their P-gp-modulating efficacy. The present analysis investigated the influence of P-gp modulators, such as verapamil, tamoxifen, droloxifene E, droloxifene Z, SDZ PSC 833 (PSC 833) and dexniguldipine in a leukemic T-cell line (CCRF-CEM) and its P-gp-resistant counterparts (CCRF-CEM/ACT400 and CCRF-CEM/VCR1000). P-gp expression was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. It was characterized as the percentage of P-gp positive cells and also expressed as a D value by using the Kolmogorov Smirnov statistic. The efficacy of P-gp modulators was determined with the rhodamine-123 accumulation test and the MTT test. An in vitro modulator concentration between 0.1 μM and 3 μM was determined, where no genuine antiproliferative effect was apparent. The modulators PSC 833 and dexniguldipine were the significant (p < C0.05) most potent chemosensitizers followed by verapamil, droloxifene Z, tamoxifen and droloxifene E in descending order. In addition to the modulators PSC 833 and dexniguldipine, droloxifene Z should especially be considered as a candidate for future ex vivo and in vivo studies. The main advantage of droloxifene Z could be the low rate of expected side effects. This fact permits the use of high Drol Z dosage in order to achieve a relevant modulating effect in vivo and to use this drug in combination with a further modulator so as to reach maximum efficacy with tolerable side effects.

Original languageEnglish
JournalLeukemia and Lymphoma
Volume31
Issue number5-6
Pages (from-to)589-597
Number of pages9
ISSN1042-8194
DOIs
Publication statusPublished - 1998

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