Abstract
Acquired resistance to multiple natural products in vitro is mediated by P-glycoprotein (Pgp). Expression of this protein has been demonstrated in some normal tissues and in tumor samples obtained from both untreated and treated patients. In situ hybridizations with RNA probes have demonstrated higher levels of expression of mdr-1/Pgp in well-differentiated tumors and in well-differentiated areas in tumors with mixed histologies. Expression of mdr-1/Pgp in human colon carcinoma cell lines was increased by the differentiating agents sodium butyrate, dimethyl sulfoxide, and dimethylformamide. In the SW-620 cell line addition of sodium butyrate resulted in a rapid induction of mdr-1/Pgp mRNA that was sustained for the duration of the exposure. The levels of P-glycoprotein were measured by immunoblotting and were also increased. Similar results were obtained in three other cell lines including the HCT-15 line. This induction occurred without alterations in nuclease sensitivity. Discontinuation of sodium butyrate was followed by a rapid fall in the levels of mRNA. The levels of P-glycoprotein returned to normal with a half-life of about 24 h. In spite of a 20-25-fold increase in the level of mdr-1/Pgp mRNA and P-glycoprotein, the SW-620 cell line did not demonstrate increased resistance to doxorubicin and vinblastine or decreased accumulation of vinblastine. In contrast, in the HCT-15 cell line, a 5-fold increase of mdr-1/Pgp was accompanied by a comparable fall in vinblastine accumulation which was reversed by verapamil. In the SW-620 cell line, the induced protein could be photolabeled using [3H]azidopine. Expression of mdr-1/Pgp appears to correlate with the degree of differentiation. However, its induction is not always accompanied by expression of the multidrug-resistance phenotype.
Highlights
Acquired resistance to multiple natural products in a frequently encounteredclinical problem, wheretolerance to vitro is mediated by P-glycoprotein (Pgp)
Tissues and in tumor samples obtained from both un- There is a large body of evidence that acquired resistance treatedandtreatedpatients
In situ hybridizations to multiple natural products in vitro is mediated by Pgp,’ a with RNA probes have demonstrated higher levels of cell surface glycoprotein originally described by Ling (4, 51, expression of mdr-l/Pgp inwell-differentiated tumors that isencoded by the mdr-1 gene [11,12,13,14,15,16,17,18,19,20,21,22]
Summary
Vol 264, No 30, Issue of October 25, pp. 1P8r0i3n1te-1d80in40U, .1S9.A89. Modulation of the Expressionof a Multidrug Resistance Gene (rndr-1/P-glycoprotein)by Differentiating Agents*. In situ hybridizations to multiple natural products in vitro is mediated by Pgp,’ a with RNA probes have demonstrated higher levels of cell surface glycoprotein originally described by Ling Previous work in our laboratory’ utilizing in situ hybridization with RNA probes to examine clinical specimens demonstrated higher levels of expression of mdr-1/Pgp in welldifferentiated tumors and in well-differentiated areas in tumors with mixed histologies. Precipitated, lyophilized, and resuspended in a running buffer comprised of 90% formamide, 5% saturated bromphenol blue, and 5%
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