SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance

P-glycoprotein (P-gp) is the plasma membrane transport pump responsible for efflux of chemotherapeutic agents from cells and is one of the systems that secures multidrug resistance (MDR) of neoplastic cells. In the present study, drug sensitive L1210 and multidrug resistant L1210/VCR (characterized...

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Bibliographic Details
Published in:	European journal of pharmaceutical sciences Vol. 14; no. 1; pp. 29 - 36
Main Authors:	Barančı́k, Miroslav, Boháčová, Vierka, Kvačkajová, Janka, Hudecová, Soňa, Križanová, Ol’ga, Breier, Albert
Format:	Journal Article
Language:	English
Published:	Shannon Elsevier B.V 01-08-2001 Elsevier
Subjects:	Animals Antineoplastic agents Antineoplastic Agents, Phytogenic - pharmacology ATP-Binding Cassette, Sub-Family B, Member 1 - physiology Biological and medical sciences Blotting, Western Cytosol - drug effects Cytosol - metabolism Drug Resistance, Multiple - genetics Enzyme Inhibitors - pharmacology General aspects Humans Imidazoles - pharmacology Leukemia L1210 - enzymology Medical sciences Mitogen-Activated Protein Kinases - antagonists & inhibitors Mouse leukaemia cells L1210 Multidrug resistance P-glycoprotein p38 Mitogen-Activated Protein Kinases p38-MAPK Pharmacology. Drug treatments Phosphorylation - drug effects Protein kinase inhibitors Pyridines - pharmacology SB203580 Signal Transduction - drug effects Tumor Cells, Cultured Vincristine Vincristine - pharmacology P-glycoprotein Multidrug resistance Mouse leukaemia cells L1210 p38-MAPK Protein kinase inhibitors SB203580 Vincristine Antineoplastic agent Enzyme Transferases P Glycoprotein Enzyme inhibitor Malignant hemopathy L1210-Leukemia Gene expression In vitro Alkaloid Protein kinase Multiple resistance Established cell line Tumor cell
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Summary:	P-glycoprotein (P-gp) is the plasma membrane transport pump responsible for efflux of chemotherapeutic agents from cells and is one of the systems that secures multidrug resistance (MDR) of neoplastic cells. In the present study, drug sensitive L1210 and multidrug resistant L1210/VCR (characterized by overexpression of P-gp) mouse leukemic cell lines were used as an experimental model. We have found that SB203580, a specific inhibitor of p38-MAPK pathway, significantly reduced the degree of the vincristine resistance in L1210/VCR cells. This phenomenon was accompanied by a decrease in the LC 50 value of vincristine from 3.203±0.521 to 0.557±0.082 μM. The LC 50 value of sensitive cells for vincristine was about 0.011 μM. The effect of SB203580 on L1210/VCR cells was associated with significantly increased intracellular accumulation of [ 3H]-vincristine in the concentration dependent manner. Prolonged exposure of resistant cells to 30 μM SB203580 did neither significantly influence the gene expression of P-gp, nor change the protein levels of p38-MAPK. Western blot analysis revealed that the MDR phenotype in L1210/VCR cells was associated with increased level and activity of cytosolic p38-MAPK. In resistant cells, the enhanced phosphorylation of both, p38-MAPK and ATF-2 (endogenous substrate for p38-MAPK) was found as well. In conclusion we could remark that SB203580, an inhibitor of p38 kinase pathway, reversed the MDR resistance of L1210/VCR cells. MDR phenotype of these cells is connected with increased levels and activities of p38-MAPK. These findings point to the possible involvement of the p38-MAPK pathway in the modulation of P-gp mediated multidrug resistance in the L1210/VCR mouse leukemic cell line. However, the mechanisms of SB203580 action should be further investigated.
ISSN:	0928-0987 1879-0720
DOI:	10.1016/S0928-0987(01)00139-7