28 September 2012
Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells
Yinghui ChenAE, Yongbo ZhaoBD, Cuicui WangC, Xia XiaoB, Xiaoyong ZhouC, Guoxiong XuAEFDOI: 10.12659/MSM.883477
Med Sci Monit 2012; 18(10): BR383-388
Abstract
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 (IC50) 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 IC50 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 IC50 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.
Keywords: Phenytoin - pharmacology, P-Glycoprotein - metabolism, Leukemia - pathology, K562 Cells, Drug Resistance, Neoplasm - drug effects, Doxorubicin - pharmacology, Dose-Response Relationship, Drug, Cell Survival - drug effects, Protein Kinase Inhibitors - pharmacology, p38 Mitogen-Activated Protein Kinases - metabolism
Editorial
01 January 2023 : Editorial
Editorial: Current Status of Two Adjuvanted Malaria Vaccines and the World Health Organization (WHO) Strategy to Eradicate Malaria by 2030DOI: 10.12659/MSM.939357
Med Sci Monit 2023; 29:e939357
SARS-CoV-2/COVID-19
26 January 2023 : Editorial
Editorial: The XBB.1.5 (‘Kraken’) Subvariant of Omicron SARS-CoV-2 and its Rapid Global SpreadMed Sci Monit In Press; DOI: 10.12659/MSM.939580
19 January 2023 : Clinical Research
Evaluation of Health-Related Quality of Life and Mental Health in 729 Medical Students in Indonesia During ...Med Sci Monit In Press; DOI: 10.12659/MSM.938892
19 January 2023 : Clinical Research
Determining the Impact of the COVID-19 Pandemic on Dental Care in the Serbian Adult Population: An Online Q...Med Sci Monit 2023; 29:e939238
27 December 2022 : Clinical Research
Effect of Physiotherapy to Correct Rounded Shoulder Posture in 30 Patients During the COVID-19 Pandemic in ...Med Sci Monit 2022; 28:e938926
In Press
31 Jan 2023 : Clinical Research
Balloon Dilation Eustachian Tuboplasty Combined with Tympanotomy Tube Insertion for Treatment of Refractory...Med Sci Monit In Press; DOI: 10.12659/MSM.938879
31 Jan 2023 : Clinical Research
Comparison of Vision Correction and Corneal Thickness at 180-Day Follow-Up After Femtosecond Laser-Assisted...Med Sci Monit In Press; DOI: 10.12659/MSM.939099
30 Jan 2023 : Clinical Research
Splenic Artery Steal Syndrome in Patients with Liver Cirrhosis: A Retrospective Clinical StudyMed Sci Monit In Press; DOI: 10.12659/MSM.938998
27 Jan 2023 : Database Analysis
Association Between Neutrophil-Lymphocyte Ratio and All-Cause Mortality in Critically Ill Patients with Chr...Med Sci Monit In Press; DOI: 10.12659/MSM.938554
Most Viewed Current Articles
13 Nov 2021 : Clinical Research
Acceptance of COVID-19 Vaccination and Its Associated Factors Among Cancer Patients Attending the Oncology ...DOI :10.12659/MSM.932788
Med Sci Monit 2021; 27:e932788
30 Dec 2021 : Clinical Research
Retrospective Study of Outcomes and Hospitalization Rates of Patients in Italy with a Confirmed Diagnosis o...DOI :10.12659/MSM.935379
Med Sci Monit 2021; 27:e935379
08 Mar 2022 : Review article
A Review of the Potential Roles of Antioxidant and Anti-Inflammatory Pharmacological Approaches for the Man...DOI :10.12659/MSM.936292
Med Sci Monit 2022; 28:e936292
01 Jan 2022 : Editorial
Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...DOI :10.12659/MSM.935952
Med Sci Monit 2022; 28:e935952