Effects of progesterone and leukotriene receptor antagonists in experimental models of P-glycoprotein-related resistance.
P-glycoprotein (P-gp)-related resistance is one of the most intensively investigated mechanisms of multidrug resistance, but the search for better modulators and better modulator combinations has just begun. The present work was performed to determine whether leukotriene LTD4 /LTE4 receptor antagonists such as FPL-55712, Ly-163443, Ly-171883, MK-571 and the progesterone receptor antagonist RU-38486 are potential P-gp modulators in models of P-gp-related resistance. Additionally, the P-gp modulating potency of the combination of RU-38486 and verapamil was investigated. P-gp expression was determined with the monoclonal antibody 4E3.16, and functional activity was assessed by the Rhodamine123 (R123) accumulation assay. Efficacy of the modulators was determined with the MTT test and the R123 accumulation assay. The in vitro examinations were done in the P-gp-resistant human T-lymphoblastic cell lines CCRF-CEM/ ACT400 and CCRF-CEM/VCR1000. No P-gp-modulating effect was observed with Ly-163443, Ly-171883, FPL-55712 or MK-571. A significant (p<0.05) cytotoxicity of the examined modulators per se (without actinomycin D or vincristine) was demonstrated only for verapamil at a concentration of 10 microM. At a concentration of 10 microM a significant (p<0.05) P-gp modulating effect was observed with RU-38486, which was even more pronounced than the effect of verapamil as determined by the MTT test. Using the R123 accumulation assay it was shown that the combination of RU-38486 (6 microM and 10 microM) and verapamil additively increased (p<0.05) the percentage of accumulating cells. This additive effect was reflected by a significantly (p<0.05) enhanced efficacy of the combination of drugs with respect to inhibition of cell proliferation. The data presented advocate testing of new potential P-gp modulator combinations, such as RU-38486 and verapamil, with the aim of increasing efficacy and simultaneously reducing side effects.
Nuessler
V
V
Klinikum Grosshadern, Medizinische Klinik und Poliklinik III Marchioninistr. 15, Munich, D-81366, Germany.
Pelka-Fleischer
R
R
Zwierzina
H
H
Wilmanns
W
W
Denzlinger
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D005456:Fluorescent Dyes; D006801:Humans; D020024:Leukotriene Antagonists; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D020112:Rhodamine 123; D012235:Rhodamines
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D020024:Leukotriene Antagonists; D011980:Receptors, Progesterone; D012235:Rhodamines; D020112:Rhodamine 123