Effect of new thioacridine derivatives on P-gp function and on mdr1 gene expression.
We studied the effect of thioacridine derivatives on the function of P-glycoprotein in MDR mouse T-lymphoma cell line L5178 and in MDR human leukemia cell line K562/ADR by rhodamine 123 uptake assay. The effect of some selected thioacridines was also investigated on the expression of the mdr1 gene. Expression was analysed by RT-PCR. Two compounds: 3-amino-9-thio-(4'-nitrobenzyl)acridinone and 2,7-dimethoxy-9-thio-(2'-diethylaminoethyl) acridinone were able to block the function of the P-gp, and also to decrease significantly mdr1 gene expression. Because these two derivatives exert their positive effects as reversing agents they could be potential candidate anticancer agents for further investigation. The thioacridines, which do not affect P-gp function, do not affect or increase the expression of mdr1 gene. Our results showed the structure-activity relationships of these compounds, providing a direction for the development of new, more active compounds.
Hevér
A
A
Department of Microbiology, Albert Szent-Györgyi Medical University, Szeged, Hungary.
Santelli-Rouvier
C
C
Brouant
P
P
el Khyari
S
S
Molnár
J
J
Barra
Y
Y
Barbe
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology*; D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D004396:Coloring Agents / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000378:metabolism; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics; D014158:Transcription, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D004396:Coloring Agents; D012334:RNA, Neoplasm; D012235:Rhodamines; D020112:Rhodamine 123