Reduced drug resistance in a multidrug resistant cell line by 5,8,11,14-eicosatetraynoic acid
Anderson, K.M.; Harris, J.E.
Research Communications in Molecular Pathology and Pharmacology 86(2): 195-203
1994
ISSN/ISBN: 1078-0297 PMID: 7881868 Document Number: 431086
We examined whether the arachidonic acid competitive antagonist, ETYA (5,8,11,14-eicosatetraynoic acid), modulated drug sensitivity in a cell line that overexpresses 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 IC-50 of 190 mu-M for both lines. ETYA (20 mu-M) increased rhodamine 123 accumulation in KB8-5-11 MDR cells but not in KB3-1 sensitive cells. Arachidonic acid at 20 mu-M did not alter rhodamine accumulation in either cell line. Increasing the concentration of ETYA from 40 to 160 mu-M or incubation beyond 30 min did not increase KB8-5-11 dye retention. Forty mu-M or more of ETYA increased KB3-11 dye retention. In a 6 day proliferation assay of KB8-5-11 cells, a nontoxic (40 mu-M) concentration of ETYA reduced the IC-50 for doxorubicin 4-fold, the IC-50 for colchicine 2-fold, but had no effect on the IC-50 for vinblastine. ETYA at 40 mu-M did not alter the IC-50 for any drug tested with KB3-1 cells. Therefore: (a) ETYA (20 or 40 mu-M) 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.