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The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance
V Gekeler1, W Ise, K H Sanders
1Byk Gulden, Konstanz, Germany.
Abstract:
The multidrug resistant cell lines HL60/AR and GLC4/ADR show high overexpression of the gene encoding the multidrug resistance associated protein MRP compared to their drug sensitive parental counterparts. This and the virtual absence of mdr1/P-glycoprotein gene expression was proven by a complementary DNA polymerase chain reaction (cDNA-PCR) approach. Applying a 72-hour tetrazolium based colorimetric MTT-assay we demonstrate on both MDR sublines a dose-dependent modulation of drug resistances by the leukotriene LTD4 receptor antagonist MK571. A complete reversal of vincristine resistances was achieved at final MK571 concentrations of 30 microM (HL60/AR) or 50 microM (GLC4/ADR) which by itself did not disturb cellular proliferation. The drug resistance of a mdr1/P-gp overexpressing multidrug-resistant HL60 subline, in contrast, was not significantly affected by MK571. Similar effects were seen using the glutathione (GSH) synthesis inhibitor buthionine sulfoximine (BSO). Our results point to a relationship between MRP and a conjugate transporter and identify MK571 as a new tool structure for developing modulators specific for a MRP associated multidrug resistance.
Insights
Multidrug resistance associated protein (MRP) overexpression in cancer cells can be modulated by MK571, a leukotriene LTD4 receptor antagonist. This finding offers a new strategy for overcoming drug resistance in specific cancer types.
Area of Science:
- Pharmacology
- Molecular Biology
- Cancer Research
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy.
- Overexpression of specific transporter proteins, like MRP, contributes to MDR.
- Understanding the mechanisms of MRP-mediated drug resistance is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of MRP in multidrug resistance.
- To evaluate the efficacy of MK571, a leukotriene LTD4 receptor antagonist, in reversing MRP-mediated drug resistance.
- To explore potential therapeutic strategies for overcoming MDR.
Main Methods:
- Utilized multidrug resistant cell lines (HL60/AR, GLC4/ADR) overexpressing MRP.
- Employed complementary DNA polymerase chain reaction (cDNA-PCR) to confirm gene expression levels.
- Applied a 72-hour tetrazolium-based colorimetric MTT assay to assess drug resistance modulation.
Main Results:
- HL60/AR and GLC4/ADR cells showed high MRP gene overexpression compared to sensitive counterparts.
- MK571 dose-dependently modulated drug resistances in MRP-overexpressing sublines.
- Complete reversal of vincristine resistance was achieved with MK571, without affecting cellular proliferation.
- MK571 did not significantly affect drug resistance in a P-glycoprotein overexpressing subline.
- Similar effects were observed with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor.
Conclusions:
- Results suggest a relationship between MRP and conjugate transporters.
- MK571 shows potential as a tool for developing modulators of MRP-associated multidrug resistance.
- This study identifies a promising avenue for overcoming specific types of drug resistance in cancer therapy.