Reversal of LRP-associated drug resistance in colon carcinoma SW-620 cells.
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.
Kitazono
M
M
Department of Cancer Chemotherapy, Institute for Cancer Research, Kagoshima University, Japan.
Okumura
H
H
Ikeda
R
R
Sumizawa
T
T
Furukawa
T
T
Nagayama
S
S
Seto
K
K
Aikou
T
T
Akiyama
S
S
D000470:Alkaloids / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D044182:Benzylisoquinolines; D002087:Butyrates / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy*; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004396:Coloring Agents / Q000494:pharmacology; D003498:Cyclic P-Oxides / Q000494:pharmacology*; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins / Q000378:metabolism*; D009539:Nicotinic Acids / Q000494:pharmacology*; D016337:RNA, Catalytic / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism*; D000099187:Major Vault Protein; D052117:Benzodioxoles
D000470:Alkaloids; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D002087:Butyrates; D004396:Coloring Agents; D003498:Cyclic P-Oxides; D004317:Doxorubicin; D005047:Etoposide; D009363:Neoplasm Proteins; D009539:Nicotinic Acids; D016337:RNA, Catalytic; D013778:Tetrazolium Salts; D013844:Thiazoles; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C103821:PAK 104P; C006947:cepharanthine; D052117:Benzodioxoles; C022616:thiazolyl blue; C019475:2-methylbutanoic acid