Function and mechanism of pyronaridine: a new inhibitor of P-glycoprotein-mediated multidrug resistance.
Abstract
AIM: To study the effect and mechanism of pyronaridine (PND) on the reversal of
multidrug resistance (MDR) in K562/A02 and MCF7/ADR cell lines with mdr1+.
METHODS: MTT assay was used to determine the cells growth inhibition after
incubation for 72 h in the presence of doxorubicin (DOX) with or without PND.
Intracellular accumulation of DOX was analyzed by spectrofluorometry.
P-glycoprotein (P-gp) activity was investigated by measuring the extrusion of the
cationic dye rhodamine 123 (Rh123). The apoptosis of cells and mdr1 gene
expression were detected using flow cytometry and RTPCR, respectively.
RESULTS: PND slightly inhibited the growth of MDR human leukemia, breast cancer
cells, and their parental cell lines. The IC50 of PND were 5.10 - 18.66
micromol/L depending on the kinds of cell lines. PND at low toxic concentrations
enhanced antiproliferative effect of DOX on MDR cells and the apoptosis induced
by DOX in a concentration-dependent manner. Intracellular accumulation of DOX and
Rh123 in MDR cell lines increased after combination with PND. PND did not
down-regulate mdr1 gene expression in MDR cell lines K562/A02 and MCF7/ADR.
CONCLUSION: As the third-generation Pgp inhibitor, PND significantly reversed MDR
in MDR cell lines K562/A02 and MCF7/ADR by inhibiting P-gp function.
Keywords:
multidrug resistance (MDR) in K562/A02 and MCF7/ADR cell lines with mdr1+.
METHODS: MTT assay was used to determine the cells growth inhibition after
incubation for 72 h in the presence of doxorubicin (DOX) with or without PND.
Intracellular accumulation of DOX was analyzed by spectrofluorometry.
P-glycoprotein (P-gp) activity was investigated by measuring the extrusion of the
cationic dye rhodamine 123 (Rh123). The apoptosis of cells and mdr1 gene
expression were detected using flow cytometry and RTPCR, respectively.
RESULTS: PND slightly inhibited the growth of MDR human leukemia, breast cancer
cells, and their parental cell lines. The IC50 of PND were 5.10 - 18.66
micromol/L depending on the kinds of cell lines. PND at low toxic concentrations
enhanced antiproliferative effect of DOX on MDR cells and the apoptosis induced
by DOX in a concentration-dependent manner. Intracellular accumulation of DOX and
Rh123 in MDR cell lines increased after combination with PND. PND did not
down-regulate mdr1 gene expression in MDR cell lines K562/A02 and MCF7/ADR.
CONCLUSION: As the third-generation Pgp inhibitor, PND significantly reversed MDR
in MDR cell lines K562/A02 and MCF7/ADR by inhibiting P-gp function.