Inhibition of the transport function of membrane proteins by some substituted phenothiazines in E. coli and multidrug resistant tumor cells.
Efflux-pumps mediated by P-glycoprotein increase the level of resistance to antibiotics in bacteria and to cytostatics in tumor cells due to decreased drug accumulation, and are also involved in the operation of blood brain barrier. Different compounds are able to enhance drug retention in the cells by inhibiting the efflux-pump mechanism of multidrug resistant (mdr) cancer cells and bacteria. The effects of substituted chlorpromazines were studied on a hemolysin producing and antibiotic resistant plasmid carrying E coli, and rhodamine uptake of multidrug resistant (mdr 1 gene expressing) mouse lymphoma cells. Hemolysin transporter protein encoding plasmids were eliminated from E. coli by a representative phenothiazine namely promethazine. Minimal inhibitory concentrations of tetracyclin and promethazine were lower for plasmidless bacteria as compared to the parent, plasmid carrying strains. The antibiotic resistance plasmid was cured of the R-plasmid of E. coli JE 2571, however, the ring substituted derivatives were less effective then parent compounds. The effect of some substituted phenothiazines on P-glycoprotein efflux-pump of mouse lymphoma cells were studied. The majority of ring substituted derivatives reversed the mdr of tumor cells. The 3,7,8-trihydroxy- and 7,8-dihydroxy derivatives of chlorpromazine were effective as P-glycoprotein blockers, however, 7,8-diacetoxy-, 7,8dimetoxy-, 7-semicarbazone-, and 5-oxo-chlorpromazine derivatives had only moderate effect. A tomato lectin, specific for blood brain capillary endothelium was able to modify the activity of P-glycoprotein in tumor cells. Phenothiazine and tomato lectin had some antagonism in tumor cells. Our results suggest that the inhibition of P-glycoprotein function in murine tumor cells and inhibition of transporter protein in E. coli bacteria may depend on pi-electron superdelocalizibility and electrophile binding of the compounds to the transporter proteins. The intracellular accumulation of antibiotics or chemotherapeutics increased as a consequence of decreased drug efflux in both bacterial and tumor cell systems. The inhibition of the drug effux-pump is the same for all individual cells of the population. These results can be realized by combination chemotherapy, however, antiplasmid effect itself cannot be exploited in this respect because the resistance was reversed in a part of the population only. The similarity with mdr P-glycoprotein in tumor cells and brain capillary endothels provides a good model for molecules opening the blood brain barrier.
Molnár
J
J
Institute of Microbiology, Albert Szent-Györgyi Medical University, Szeged, Hungary.
Hevér
A
A
Fakla
I
I
Fischer
J
J
Ocsovski
I
I
Aszalós
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001812:Blood-Brain Barrier; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D018432:Drug Resistance, Multiple; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D006460:Hemolysin Proteins / Q000502:physiology*; D051379:Mice; D010640:Phenothiazines / Q000494:pharmacology*; D010957:Plasmids; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D006460:Hemolysin Proteins; D010640:Phenothiazines