MRP is frequently expressed in human lung-cancer cell lines, in non-small-cell lung cancer and in normal lungs.
The multidrug resistance-associated protein (MRP), a new membrane transporter related to non-Pgp multidrug resistance, is overexpressed in some drug-selected cancer-cell lines. The role of MRP in unselected cell lines and in human cancer is unknown. MRP gene expression, determined by RNase protection assay and chemosensitivity to doxorubicin, etoposide and cisplatin, determined by MTT assay, were assessed in 18 non-drug-selected lung-cancer cell lines (10 small-cell lung cancer, 6 non-small-cell lung cancer, and 1 carcinoid). MRP gene expression was also investigated in normal lung tissue and primary non-small-cell lung cancer. All cell lines except one and all normal lung tissues and primary non-small-cell lung cancers expressed detectable levels of MRP. Expression was significantly lower in cell lines than in normal and neoplastic lung. MRP protein expression was also assessed by immunohistochemistry using the monoclonal antibody MRPr1; comparable levels of expression were observed between mRNA and protein in cell lines; however, in tumor samples intense staining was observed in tumor cells as well as in infiltrating normal cells in tumors, making the results less comparable to those obtained by RNase expression. MRP expression did not directly correlate with function in a calcein accumulation assay in 2 unselected cell lines. No gene amplification was observed by Southern-blot analysis, in the unselected cell lines or in tumor samples. In general, in cell lines, MRP gene expression was correlated with lower chemosensitivity to doxorubicin and etoposide, but not to cisplatin. However, MRP expression did not directly correlate with MRP function as assessed by a calcein accumulation assay in one of 2 unselected cell lines examined. Our results suggest that MRP may be implicated in drug resistance in unselected lung-cancer cell lines and its role in normal lung and primary lung cancer warrants further investigation in patients undergoing chemotherapy.
Giaccone
G
G
Department of Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
van Ark-Otte
J
J
Rubio
G J
GJ
Gazdar
A F
AF
Broxterman
H J
HJ
Dingemans
A M
AM
Flens
M J
MJ
Scheper
R J
RJ
Pinedo
H M
HM
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000378:metabolism / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002945:Cisplatin; D018076:DNA, Complementary; D004317:Doxorubicin; D005047:Etoposide; D005452:Fluoresceins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C007740:fluorexon