Enhanced therapeutic effects on the multi-drug resistant human leukemia cells in vitro and xenograft in mice using the stealthy liposomal vincristine plus quinacrine.
The multi-drug resistance (MDR) could be caused by the over-expression of adenosine triphosphate binding cassette transporters such as p-glycoprotein, thereby resulting in the efflux of anti-cancer drugs from the cells. An anti-resistant stealthy liposomal vincristine plus quinacrine was defined in this study. Human chronic myelogenous leukemia K562 and MDR K562 cells were included for comparisons. Anti-tumor activity studies were performed on female BALB/c nude mice with MDR K562 cell xenografts. Results showed that quinacrine was effective in reversing the resistance in the MDR K562 cells, and enhanced the anti-tumor effect of vincristine in K562 cells. The caspase-9 and -3 activities in the MDR K562 and K562 cells were increased with the dose rise of quinacrine. In the MDR K562 cell xenografts in mice, the anti-resistant tumor effect of the stealthy liposomal vincristine plus quinacrine was evidently observed. The enhanced anti-tumor effects of vincristine by quinacrine in the resistant/non-resistant K562 cells could be because of the direct injury and the potentiating apoptotic effect of vincristine via activating the initiator caspase-9 and subsequently the effector caspase-3, and the long circulatory effect of stealthy liposomes. The stealthy liposomal encapsulation of vincristine plus quinacrine could be a potential therapeutic approach for resistant human leukemia.
Liang
Gong-Wen
GW
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
Lu
Wan-Liang
WL
Wu
Jin-Wei
JW
Zhao
Ji-Hui
JH
Hong
Hai-Yan
HY
Long
Chuan
C
Li
Ting
T
Zhang
Yu-Teng
YT
Zhang
Hua
H
Wang
Jian-Cheng
JC
Zhang
Xuan
X
Zhang
Qiang
Q
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011796:Quinacrine / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000008:administration & dosage
D008081:Liposomes; D014750:Vincristine; D020169:Caspases; D011796:Quinacrine