Avermectins inhibit multidrug resistance of tumor cells.
The modification of the sensitivity of Hep-2 and P388 tumor cells to taxol and vincristine, substrates of multidrug resistance proteins, by naturally occurring avermectins and the effect of avermectins on the accumulation of calcein in cells and the efflux of rhodamine 123 were studied. While avermectins did not affect the sensitivity of tumor cells to hydrogen peroxide and cisplatin, they significantly enhanced the sensitivity of cells of both wild-type and resistant strains to taxol and vincristine. The coefficients of modification for resistant strains were substantially higher. Avermectins suppressed the efflux of rhodamine 123 from cells and increased the accumulation of calcein in cells. The relative inhibitory activity of avermectins depended on the cell type and on the substrate of multidrug resistance proteins whose transport they suppressed (vincristine, taxol, rhodamine 123, calcein acetoxymethyl ester). The least active was avermectin B1 or ivermectin; the most active avermectins varied depending on the substrate and the cell type. In the case of vincristine transport, the most active avermectin was almost by one order of magnitude more effective than the traditional inhibitor of multidrug resistance cyclosporin A. This property of avermectins can be used in tumor therapy by combining application of avermectins with antitumor preparations, the substrates of multidrug resistance proteins.
Korystov
Yuri N
YN
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russian Federation. ykorystov@rambler.ru
Ermakova
Natalia V
NV
Kublik
Ludmila N
LN
Levitman
Maria Kh
MKh
Shaposhnikova
Vera V
VV
Mosin
Vladimir A
VA
Drinyaev
Viktor A
VA
Kruglyak
Elena B
EB
Novik
Tamara S
TS
Sterlina
Tatiana S
TS
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology*; D004357:Drug Synergism; D005452:Fluoresceins / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D007941:Leukemia P388 / Q000473:pathology; D008297:Male; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D020112:Rhodamine 123 / Q000378:metabolism / Q000494:pharmacology; D012426:Russia; D014750:Vincristine / Q000494:pharmacology
D004338:Drug Combinations; D005452:Fluoresceins; D020112:Rhodamine 123; D014750:Vincristine; D007559:Ivermectin; C019264:avermectin; D016572:Cyclosporine; D017239:Paclitaxel; C007740:fluorexon