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Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells

BACKGROUND: Several studies have shown that multidrug transporters, such as P-glycoprotein (PGP), are involved in cell resistance to chemotherapy and refractory epilepsy. The p38 mitogen-activated protein kinase (MAPK) signaling pathway may increase PGP activity. However, p38-mediated drug resistanc...

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Autores principales: Chen, Yinghui, Zhao, Yongbo, Wang, Cuicui, Xiao, Xia, Zhou, Xiaoyong, Xu, Guoxiong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Scientific Literature, Inc. 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560559/
https://www.ncbi.nlm.nih.gov/pubmed/23018344
http://dx.doi.org/10.12659/MSM.883477
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author Chen, Yinghui
Zhao, Yongbo
Wang, Cuicui
Xiao, Xia
Zhou, Xiaoyong
Xu, Guoxiong
author_facet Chen, Yinghui
Zhao, Yongbo
Wang, Cuicui
Xiao, Xia
Zhou, Xiaoyong
Xu, Guoxiong
author_sort Chen, Yinghui
collection PubMed
description BACKGROUND: Several studies have shown that multidrug transporters, such as P-glycoprotein (PGP), are involved in cell resistance to chemotherapy and refractory epilepsy. The p38 mitogen-activated protein kinase (MAPK) signaling pathway may increase PGP activity. However, p38-mediated drug resistance associated with PGP is unclear. Here, we investigated p38-mediated doxorubicin-induced drug resistance in human leukemia K562 cells. MATERIAL/METHODS: The expression of PGP was detected by RT-PCR, Western blot, and immunocytochemistry. Cell viability and half-inhibitory concentrations (IC(50)) were determined by CCK-8 assay. The intracellular concentration of drugs was measured by HPLC. RESULTS: A doxorubicin-induced PGP overexpression cell line, K562/Dox, was generated. The p38 inhibitor SB202190 significantly decreased MDR1 mRNA expression, as well as PGP, in K562/Dox cells. The IC(50) of phenytoin sodium and doxorubicin in K562/Dox cells was significantly higher than that in wild-type K562 cells, indicating the drug resistance of K562/Dox cells. During the blocking of p38 activity in the presence of SB202190, cell number was significantly reduced after the phenytoin sodium and doxorubicin treatment, and the IC(50) of phenytoin sodium and doxorubicin was decreased in K562/Dox cells. HPLC showed that the intracellular levels of phenytoin sodium and doxorubicin were significantly lower in K562/Dox cells than those in K562 cells. The decrease of the intracellular level of these drugs was significantly abolished in the presence of SB202190. CONCLUSIONS: Our study demonstrated that p38 is, at least in part, involved in doxorubicin-induced drug resistance. The mechanistic study of MAPK-mediated PGP and the action of SB202190 need further investigation.
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spelling pubmed-35605592013-04-24 Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells Chen, Yinghui Zhao, Yongbo Wang, Cuicui Xiao, Xia Zhou, Xiaoyong Xu, Guoxiong Med Sci Monit Basic Research BACKGROUND: Several studies have shown that multidrug transporters, such as P-glycoprotein (PGP), are involved in cell resistance to chemotherapy and refractory epilepsy. The p38 mitogen-activated protein kinase (MAPK) signaling pathway may increase PGP activity. However, p38-mediated drug resistance associated with PGP is unclear. Here, we investigated p38-mediated doxorubicin-induced drug resistance in human leukemia K562 cells. MATERIAL/METHODS: The expression of PGP was detected by RT-PCR, Western blot, and immunocytochemistry. Cell viability and half-inhibitory concentrations (IC(50)) were determined by CCK-8 assay. The intracellular concentration of drugs was measured by HPLC. RESULTS: A doxorubicin-induced PGP overexpression cell line, K562/Dox, was generated. The p38 inhibitor SB202190 significantly decreased MDR1 mRNA expression, as well as PGP, in K562/Dox cells. The IC(50) of phenytoin sodium and doxorubicin in K562/Dox cells was significantly higher than that in wild-type K562 cells, indicating the drug resistance of K562/Dox cells. During the blocking of p38 activity in the presence of SB202190, cell number was significantly reduced after the phenytoin sodium and doxorubicin treatment, and the IC(50) of phenytoin sodium and doxorubicin was decreased in K562/Dox cells. HPLC showed that the intracellular levels of phenytoin sodium and doxorubicin were significantly lower in K562/Dox cells than those in K562 cells. The decrease of the intracellular level of these drugs was significantly abolished in the presence of SB202190. CONCLUSIONS: Our study demonstrated that p38 is, at least in part, involved in doxorubicin-induced drug resistance. The mechanistic study of MAPK-mediated PGP and the action of SB202190 need further investigation. International Scientific Literature, Inc. 2012-10-01 /pmc/articles/PMC3560559/ /pubmed/23018344 http://dx.doi.org/10.12659/MSM.883477 Text en © Med Sci Monit, 2012 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.
spellingShingle Basic Research
Chen, Yinghui
Zhao, Yongbo
Wang, Cuicui
Xiao, Xia
Zhou, Xiaoyong
Xu, Guoxiong
Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells
title Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells
title_full Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells
title_fullStr Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells
title_full_unstemmed Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells
title_short Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells
title_sort inhibition of p38 mapk diminishes doxorubicin-induced drug resistance associated with p-glycoprotein in human leukemia k562 cells
topic Basic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560559/
https://www.ncbi.nlm.nih.gov/pubmed/23018344
http://dx.doi.org/10.12659/MSM.883477
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