VARIABLE EFFECTS OF SODIUM-BUTYRATE ON THE EXPRESSION AND FUNCTION OFTHE MDR1 (P-GLYCOPROTEIN) GENE IN COLON-CARCINOMA CELL-LINES

Expression of the MDR1 (P-glycoprotein) gene confers resistance to sev eral classes of chemotherapeutic drugs (multi-drug resistance). Colon carcinomas frequently express high levels of MDR1 mRNA and P-glycoprot ein, presumably reflecting the origin of these tumors from MDR1-expres sing normal colonic cells. In 4 colon carcinoma cell lines (SW 620, HC T-15, DLD-1, LS 180), MDR1 expression was reported in an earlier study to be elevated after exposure to a differentiating agent, sodium buty rate (NaB). In one of these cell lines (SW 620), increased MDR1 expres sion reportedly was not accompanied by a decrease in the accumulation or cytotoxicity of vinblastine, a P-glycoprotein-transported drug, sug gesting a possible functional abnormality of NaB-induced P-glycoprotei n. We have re-examined the effect of NaB on MDR1/P-glycoprotein expres sion and function in the same colon carcinoma cell lines. NaB treatmen t induced differentiation-related changes and increased expression of MDR1 mRNA in all 4 cell lines. A major increase in MDR1 mRNA and P-gly coprotein expression was observed in only one line, SW 620. This incre ase, however, was accompanied by a commensurate increase in the activi ty of P-glycoprotein, indicating that the induced protein was fully fu nctional. NaB treatment caused a relatively minor increase in MDR1 mRN A expressed in the other 3 cell lines. Two of these lines showed a det ectable increase in the P-glycoprotein expression and function, but in the third line (LS 180) P-glycoprotein was undetectable either before or after exposure to NaB. The magnitude of MDR1 induction by NaB show ed no apparent correlation with differentiation-related changes induce d by this agent. (C) 1993 Wiley-Liss, Inc.