Increase in doxorubicin cytotoxicity by inhibition of P-glycoprotein activity with lomerizine

被引:16
|
作者
Shiraki, N [1 ]
Hamada, A [1 ]
Ohmura, T [1 ]
Tokunaga, J [1 ]
Oyama, N [1 ]
Nakano, M [1 ]
机构
[1] Kumamoto Univ Hosp, Dept Pharm, Kumamoto 8608556, Japan
关键词
lomcrizine; doxorubicin; P-glycoprotein; multidrug resistance;
D O I
10.1248/bpb.24.555
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Acquired resistance to chemotherapy is a major problem during cancer treatment. One mechanism for drug resistance is overexpression of the MDR (multidrug resistance)l gene encoding the transmembrane efflux pump, P-glycoprotein (P-gp), Calcium channel blockers such as verapamil, nifedipine and nicardipine have been shown to reverse cellular drug resistance by inhibiting P-gp drug efflux. This study evaluated whether a new calcium channel blocker, lomerizine, influenced doxorubicin (Dox) cytotoxicity and P-gp activity in a P-Kp-expressing cell line compared to a non-expressing subline. Verapamil, and even more markedly; lomerizine, increased cellular uptake of calcein transported by P-gp in a P-gp-expressing erythroleukemia cell line, K562-Dos. Ten muM of lomerizine reduced the IC50 of doxorubicin in the K562-Dox from 60000 ng/ml to 800 ng/ml, whereas the IC50 of doxorubicin in the K562 subline was only marginally affected by these drugs. Lomerizine showed greater reduction in P-gp efflux than verapamil at an equimolar concentration, These results suggest that lomerizine has the clinical potential to reverse tumor MDR involving the efflux protein P-gp.
引用
收藏
页码:555 / 557
页数:3
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