Function and mechanism of pyronaridine: a new inhibitor of P-glycoprotein-mediated multidrug resistance.
OBJECTIVE
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.


CONCLUSIONS
As the third-generation Pgp inhibitor, PND significantly reversed MDR in MDR cell lines K562/A02 and MCF7/ADR by inhibiting P-gp function.
Qi
Jing
J
State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Yang
Chun-Zheng
CZ
Wang
Cai-Yun
CY
Wang
Shu-Bin
SB
Yang
Ming
M
Wang
Jin-Hong
JH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D020014:K562 Cells; D009287:Naphthyridines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009287:Naphthyridines; D004317:Doxorubicin; C027871:pyronaridine