Reduced drug resistance in a multidrug resistant cell line by 5,8,11,14-eicosatetraynoic acid.
We examined whether the arachidonic acid competitive antagonist, ETYA (5,8,11,14-eicosatetraynoic acid), modulated drug sensitivity in a cell line that over-expresses the multiple drug resistance protein, MDR1. ETYA was nontoxic to drug-sensitive parental KB3-1 cells or drug-resistant MDR KB8-5-11 cells, with an IC50 of 190 microM for both lines. ETYA (20 microM) increased rhodamine 123 accumulation in KB8-5-11 MDR cells but not in KB3-1 sensitive cells. Arachidonic acid at 20 microM did not alter rhodamine accumulation in either cell line. Increasing the concentration of ETYA from 40 to 160 microM or incubation beyond 30 min did not increase KB8-5-11 dye retention. Forty microM or more ETYA increased KB3-11 dye retention. In a 6 day proliferation assay of KB8-5-11 cells, a nontoxic (40 microM) concentration of ETYA reduced the IC50 for doxorubicin 4-fold, the IC50 for colchicine 2-fold, but had no effect on the IC50 for vinblastine. ETYA at 40 microM did not alter the IC50 for any drug tested with KB3-1 cells. Therefore: (a) ETYA (20 or 40 microM) modulated resistance of KB8-5-11 cells to several drugs to a limited extent, without potentiating toxicity in the parental line, while arachidonic acid did not. (b) Since cationic rhodamine 123 is concentrated in mitochondria, the extent is dependent upon the transmembrane potential, and increased dye retention due to ETYA may in part be related to altered ETYA-induced cell membrane potential.
Anderson
K M
KM
Department of Biochemistry, Rush Medical College, Chicago, IL 60612.
Harris
J E
JE
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D005456:Fluorescent Dyes; D012235:Rhodamines; D015117:5,8,11,14-Eicosatetraynoic Acid; D020112:Rhodamine 123; D016718:Arachidonic Acid