Mechanisms regulating cell resistance to adriamycin. Evidence that drug accumulation in resistant cells is modulated by phosphorylation of a plasma membrane glycoprotein.
Incubation of adriamycin resistant Chinese hamster lung cells with the calmodulin inhibitor trifluoperazine (TFP) resulted in a significant increase in the cellular accumulation of drug. When resistant cells were prelabeled with 32Pi and then treated with TFP, a major increase also occurred in the phosphorylation of a plasma membrane glycoprotein (P-180). The concentration of TFP required for inducing the superphosphorylation of this protein correlated well with the TFP concentration required for inducing an increase in drug accumulation in resistant cells. In addition to TFP, the Ca2+ channel blocker verapamil also induced drug uptake and enhanced the phosphorylation level of P-180. Additional studies showed that, when resistant cells reverted to drug sensitivity, there was a parallel loss in the TFP-induced P-180 phosphorylation. The results of this study indicate that the trifluoperazine-induced uptake of drug in resistant cells is mediated by a mechanism which involves an enhanced phosphorylation of P-180. It is suggested that, when this protein is superphosphorylated, it becomes biologically inactive, and that this results in the conversion of the resistant cell to one having a drug sensitive phenotype.
D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology; D004351:Drug Resistance; D005033:Ethylmaleimide / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D010766:Phosphorylation; D014268:Trifluoperazine / Q000494:pharmacology
D006023:Glycoproteins; D008565:Membrane Proteins; D014268:Trifluoperazine; D004317:Doxorubicin; D005033:Ethylmaleimide