title: Increase in doxorubicin cytotoxicity by inhibition of P-glycoprotein activity with lomerizine.
abstract: 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 microM 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.
authors.affiliation: Department of Pharmacy, Kumamoto University Hospital, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Shiraki
authors.forename: A
authors.initials: A
authors.lastname: Hamada
authors.forename: T
authors.initials: T
authors.lastname: Ohmura
authors.forename: J
authors.initials: J
authors.lastname: Tokunaga
authors.forename: N
authors.initials: N
authors.lastname: Oyama
authors.forename: M
authors.initials: M
authors.lastname: Nakano
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D010879:Piperazines / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D005452:Fluoresceins; D010879:Piperazines; D020112:Rhodamine 123; D004317:Doxorubicin; D014700:Verapamil; C052424:lomerizine; C007740:fluorexon