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Molecules 2014, 19(9), 13061-13075; doi:10.3390/molecules190913061

Effects of P-Glycoprotein and Its Inhibitors on Apoptosis in K562 Cells

1
Department of Health Statistics, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
2
HUYA Bioscience International LLC, 3 Haidian Avenue, Haidian District, Beijing 100080, China
3
Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, 280 Waihuandong Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China
4
Biotherapy Center of Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tiyuanbei, Huanhuxi Road, Hexi District, Tianjin 300060, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 5 June 2014 / Revised: 12 August 2014 / Accepted: 18 August 2014 / Published: 25 August 2014
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [915 KB, uploaded 25 August 2014]   |  

Abstract

P-glycoprotein (P-gp) is a major factor in multidrug resistance (MDR) which is a serious obstacle in chemotherapy. P-gp has also been implicated in causing apoptosis of tumor cells, which was shown to be another important mechanism of MDR recently. To study the influence of P-gp in tumor cell apoptosis, K562/A cells (P-gp+) and K562/S cells (P-gp−) were subjected to doxorubicin (Dox), serum withdrawal, or independent co-incubation with multiple P-gp inhibitors, including valspodar (PSC833), verapamil (Ver) and H108 to induce apoptosis. Apoptosis was simultaneously detected by apoptotic rate, cell cycle by flow cytometry and cysteine aspartic acid-specific protease 3 (caspase 3) activity by immunoassay. Cytotoxicity and apoptosis induced by PSC833 were evaluated through an MTT method and apoptosis rate, and cell cycle combined with caspase 3 activity, respectively. The results show that K562/A cells are more resistant to apoptosis and cell cycle arrest than K562/S cells after treatment with Dox or serum deprivation. The apoptosis of K562/A cells increased after co-incubation with each of the inhibitors of P-gp. P-gp inhibitors also enhanced cell cycle arrest in K562/A cell. PSC833 most strikingly decreased viability and led to apoptosis and S phase arrest of cell cycle in K562/A cells. Our study demonstrates that P-gp inhibits the apoptosis of tumor cells in addition to participating in the efflux of intracellular chemotherapy drugs. The results of the caspase 3 activity assay also suggest that the role of P-gp in apoptosis avoidance is caspase-related. View Full-Text
Keywords: P-glycoprotein; apoptosis; K562 cells; P-glycoprotein inhibitors; caspase 3; PSC833; verapamil; H108 P-glycoprotein; apoptosis; K562 cells; P-glycoprotein inhibitors; caspase 3; PSC833; verapamil; H108
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Zu, Y.; Yang, Z.; Tang, S.; Han, Y.; Ma, J. Effects of P-Glycoprotein and Its Inhibitors on Apoptosis in K562 Cells. Molecules 2014, 19, 13061-13075.

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