Reversal of multidrug-resistance in human leukemia cell line K562/A02 by a cyclosporin D analogue PSC 833.
- Author:
Hui DAI
1
;
Shaokai LUO
;
Aihua YIN
;
Aihua PENG
Author Information
- Publication Type:Journal Article
- MeSH: ATP-Binding Cassette, Sub-Family B, Member 1; drug effects; genetics; metabolism; Calcium Channel Blockers; pharmacology; Cyclosporine; pharmacology; Cyclosporins; pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; K562 Cells; cytology; drug effects; metabolism; RNA, Messenger; drug effects; genetics; metabolism; Verapamil; pharmacology
- From: Chinese Journal of Hematology 2002;23(1):23-26
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVETo explore the efficacy of PSC 833 on multidrug resistance (MDR) reversal and its mechanism.
METHODSHuman erythroleukemic cell line K562 and its doxorubicin-resistant counterpart K562/A02 were used in the study. Cytotoxicity was assessed by MTT assay, P-gp expression by direct immunofluorescence and mdr1 mRNA expression by reverse transcriptase polymerase chain reaction (RT-PCR) with beta-actin as internal control. Intracellular DNR retention was measured with flow cytometry.
RESULTSK562/A02 cells displayed high levels of mdr1 mRNA and P-glycoprotein and reduced DNR retention compared to their parental K562 cells. 1 micromol/L of PSC 833 had no effect on the levels of mdr1 mRNA and P-gp expression in K562/A02 cells (P > 0.05). PSC 833 conferred a dose-dependent increase on chemosensitivity of K562/A02 to DNR, and its effect was at least 3-fold more potent than that of CsA or Ver. PSC 833 could increase DNR retention in K562/A02 cells. A 100.9% restoration of intracellular DNR retention of the level of K562 cells was gained by PSC 833 at 1.0 micromol/L in K562/A02 cells, whereas only a 86.9% restoration of DNR retention was obtained by CsA at 10 micromol/L in the K562/A02 cells. No effect on DNR sensitivity and retention was found in K562 cells (P > 0.05).
CONCLUSIONPSC 833 is at least 3 approximately 10 fold more potent than CsA or Ver with respect to MDR reversing activity, and it may function by inhibiting the function of P-gp and not reducing the levels of mdr1 mRNA and P-gp directly.
