Increase in Doxorubicin Cytotoxicity by Inhibition of P-glycoprotein Activity with Lomerizine

概要

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Acquired resistance to chemotherapy is a major problem during cancer treatment. One mechanism for drug resistance is overexpression of the MDR (multidrug resistance) 1 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-gp-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-Dox. Ten μM of lomerizine reduced the IC_50 of doxorubicin in the K562-Dox from 60000ng/ml to 800ng/ml, whereas the IC_50 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.
公益社団法人日本薬学会の論文
2001-05-01