Involvement of ABC transporters in chemosensitivity of human renal cell carcinoma, and regulation of MRP2 expression by conjugated bilirubin.
In this study, the involvement of ATP-binding cassette (ABC) transporters in in vitro chemosensitivity of surgically removed human renal cell carcinomas was investigated. The relative expression levels of transporter mRNAs in the renal tumors from 13 patients were similar to those in the surrounding normal kidney tissues. Five renal cell carcinomas cultured successfully in vitro for 14 days showed significantly decreased expression of multi-drug resistance-associated proteins 2 and 6 (MRP2 and MRP6) mRNAs. In vitro chemosensitivity testing of the same specimens using the collagen-gel matrix assay indicated that some anticancer drugs were effective, especially cisplatin, which is an MRP2 substrate. MRP2 mRNA expression in renal carcinoma was significantly increased when cells were cultured in the presence of conjugated bilirubin. In an established renal proximal tubule epithelial cell line (RPTEC), conjugated bilirubin increased MRP2 expression at the mRNA and protein levels, and decreased the cisplatin sensitivity of the cells. These results indicate that MRP2 expression in renal cell carcinoma may be regulated by conjugated bilirubin in the body and decreased during in vitro culture. Thus, the effectiveness of anticancer drugs selected on the basis of in vitro chemosensitivity testing of clinical cancers may be overestimated.
Nomura
Masaaki
M
Department of Pharmacy, Kanazawa University Hospital, Kanazawa, Japan.
Matsunami
Toshio
T
Kobayashi
Kayoko
K
Uchibayashi
Tadao
T
Koshida
Kiyoshi
K
Tanaka
Motohiro
M
Namiki
Mikio
M
Mizuhara
Yasuharu
Y
Akiba
Tetsuo
T
Yokogawa
Koichi
K
Moritani
Shuzo
S
Miyamoto
Ken-Ichi
K
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001663:Bilirubin / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001663:Bilirubin; D002945:Cisplatin; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C102029:ABCC6 protein, human