Pyronaridine, a novel modulator of P-glycoprotein-mediated multidrug resistance in tumor cells in vitro and in vivo.
One of the major mechanisms of multidrug resistance (MDR) in cancer therapy is the overexpression of P-glycoprotein (Pgp). We previously reported that pyronaridine (PND), a synthetic quinoline derivative in the clinic for the treatment of malaria infections, was capable of reversing MDR phenotype in Pgp-overexpressing tumor cells. Here we further evaluated the reversal activity of PND using two Pgp-overexpressing human tumor cell lines: K562/A02 and MCF-7/ADR. PND significantly enhanced the sensitivity of K562/A02 and MCF-7/ADR cells to doxorubicin (DOX), but had no such effect on the parent K562 and MCF-7 cells. The MDR-modulating effect of PND persisted for longer than 24h after removal of the agent from the culture. In nude mice bearing K562/A02 xenografts PND significantly enhanced the antitumor activity of DOX when given intraperitoneally or orally without increasing the toxicity of DOX. Our observations suggest that PND represents a promising agent for overcoming MDR in cancer therapy.
Qi
Jing
J
State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
Wang
Shubin
S
Liu
Guying
G
Peng
Hui
H
Wang
Jinhong
J
Zhu
Zhenping
Z
Yang
Chunzheng
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D000962:Antimalarials / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009287:Naphthyridines / Q000378:metabolism*; D010641:Phenotype; D014700:Verapamil / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000962:Antimalarials; D009287:Naphthyridines; D004317:Doxorubicin; D014700:Verapamil; C027871:pyronaridine