Preliminary studies on phenothiazine-mediated reversal of multidrug resistance in mouse lymphoma and COLO 320 cells.
The ability of phenothiazine derivatives to inhibit the transport activity of P-glycoprotein in resistant mouse lymphoma and MDR/COLO 320 cells was studied. A rhodamine 123 efflux from the above-mentioned neoplastic cells in the presence of tested compounds was examined by flow cytometry. Two of the phenothiazine derivatives, namely perphenazine and prochlorperazine dimaleate, proved to be effective inhibitors of the rhodamine efflux. Other tested phenothiazine derivatives (promethazine hydrochloride, oxomemazine, methotrimeprazine maleate, trifluoropromazine hydrochloride, trimeprazine) also modulated the intracellular drug accumulation in both resistant cell lines, however, they exerted additional cytotoxic effects. The differences observed between the effects of the test compounds on intracellular drug accumulation could be the outcome of differences in phenothiazine's chemical structure, which is crucial for drug-cell membrane interactions. The results of this study provide information about a new group of compounds that offer promise in multidrug resistance reversal in tumor cells.
Pajak
Beata
B
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw Agricultural University, ul. Nowoursynowska 159, 02-776 Warsaw, Poland.
Molnar
Joseph
J
Engi
Helga
H
Orzechowski
Arkadiusz
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D015394:Molecular Structure; D010546:Perphenazine / Q000737:chemistry / Q000494:pharmacology; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D011346:Prochlorperazine / Q000737:chemistry / Q000494:pharmacology; D012235:Rhodamines / Q000037:antagonists & inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D010640:Phenothiazines; D012235:Rhodamines; D010546:Perphenazine; D011346:Prochlorperazine