Inhibition of the MDR1 transporter by new phenothiazine derivatives.
The MDR1 transporter mediated efflux of different xenobiotics out of the cells serves as the most important mechanisms of the multidrug resistance in cancer cells, thus inhibition of the MDR1 transporter may increase the efficiency of anticancer drugs in the therapy. Here we describe some new phenothiazine derivatives, which possess strong in vitro MDR1 inhibitory activity. The effectiveness of the compounds on the MDR1 mediated calcein-AM efflux, ATPase activity, and colchicine resistance was proven by microplate assays and flow cytometry using recombinant and control cell lines. Some of these derivatives were more active than verapamil and one of them was at least as active as cyclosporin A. According to our results the new structural elements built in these phenothiazine type compounds increased their MDR1 inhibitory activity, which may serve as a basis of the development of an effective MDR1 inhibitor drug.
Kónya
Attila
A
IVAX Drug Research Institute, Berlini u. 47-49, 1045 Budapest, Hungary. h8773kon@ella.hu
Andor
Attila
A
Sátorhelyi
Péter
P
Németh
Klára
K
Kurucz
István
I
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D003001:Cloning, Molecular; D003078:Colchicine / Q000037:antagonists & inhibitors; D004285:Dogs; D004351:Drug Resistance / Q000187:drug effects; D005434:Flow Cytometry; D005452:Fluoresceins / Q000378:metabolism; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D010640:Phenothiazines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005452:Fluoresceins; D010640:Phenothiazines; C085925:calcein AM; D003078:Colchicine