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Reversal of LRP‐associated drug resistance in colon carcinoma sw‐620 cells
Author(s) -
Kitazono Masaki,
Okumura Hiroshi,
Ikeda Ryuji,
Sumizawa Tomoyuki,
Furukawa Tatsuhiko,
Nagayama Shuichi,
Seto Kiyotomo,
Aikou Takashi,
Akiyama Shinichi
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(20010101)91:1<126::aid-ijc1018>3.0.co;2-8
Subject(s) - efflux , sodium butyrate , multiple drug resistance , p glycoprotein , cell culture , microbiology and biotechnology , drug resistance , chemistry , cytoplasm , butyrate , cancer research , biology , biochemistry , fermentation , genetics
Resistance to multiple drugs is mediated by lung resistance‐related protein (LRP) as well as P‐glycoprotein (P‐gp) and multidrug resistance protein (MRP). The levels of expression of LRP mRNA and LRP in a human colon carcinoma cell line, SW‐620, were increased by the differentiation‐inducing agent, sodium butyrate (NaB). Treatment of SW‐620 cells with NaB for 2 weeks conferred resistance to adriamycin (ADM) and VP‐16. The resistance was almost completely reversed by PAK‐104P, a pyridine analog, but not by cepharanthine. ADM accumulated mainly in the nuclei of SW‐620 cells not treated with NaB and in the cytoplasm of SW‐620 cells treated with NaB. When the NaB‐treated SW‐620 cells were incubated with ADM in the presence of PAK‐104P, the accumulation of ADM in nuclei was substantially increased. Isolated nuclei from untreated cells accumulated more ADM than nuclei from NaB‐treated cells. Efflux of ADM from the nuclei isolated from NaB‐treated cells was enhanced. PAK‐104P and an antibody against LRP increased the accumulation of ADM in the isolated nuclei from NaB‐treated cells, and inhibited the enhanced efflux of ADM from the nuclei. These findings suggest that at least in part, PAK‐104P reverses LRP‐mediated drug resistance by inhibiting the efflux of ADM from nuclei. PAK‐104P may be useful for reversing MDR in tumors that overexpress LRP. Int. J. Cancer 91:126–131, 2001. © 2001 Wiley‐Liss, Inc.