Modulation of P-glycoprotein phosphorylation and drug transport by sodium butyrate.
P-Glycoprotein (Pgp) expression in cell lines derived from tumors arising from cells which normally express Pgp can be increased by sodium butyrate and other differentiating agents. Although the Pgp level increased 25-fold after sodium butyrate treatment in SW620 human colon carcinoma cells, the intracellular accumulation of vinblastine, adriamycin, and actinomycin D increased rather than decreased. In contrast, colchicine showed the expected decrease in accumulation, as a result of increased efflux. Likewise, treatment of a Pgp-expressing multidrug-resistant SW620 subline with sodium butyrate resulted in active interference with Pgp function. This effect was partially reversed by phorbol esters with a resulting decrease in the accumulation of vinblastine, adriamycin, and actinomycin D. Sodium butyrate, while increasing Pgp levels, inhibited the phosphorylation of Pgp. Time course studies revealed a tight relationship between decreased Pgp phosphorylation and increased vinblastine accumulation after sodium butyrate treatment. Either treatment with phorbol esters or withdrawal of sodium butyrate increased Pgp phosphorylation while decreasing vinblastine accumulation. These studies suggest that the specificity of Pgp transport can be modulated by phosphorylation and that vinblastine, adriamycin, or actinomycin D transport, but not that of colchicine, is diminished after dephosphorylation by sodium butyrate.
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
S E
SE
Bates
S J
SJ
Currier
M
M
Alvarez
A T
AT
Fojo
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001692:Biological Transport / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002460:Cell Line; D003078:Colchicine / Q000378:metabolism; D003609:Dactinomycin / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014747:Vinblastine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002087:Butyrates; D008562:Membrane Glycoproteins; D010703:Phorbol Esters; D010750:Phosphoproteins; D020148:Butyric Acid; D003609:Dactinomycin; D014747:Vinblastine; D004317:Doxorubicin; D003078:Colchicine