Pharmacogenomics approach reveals MRP1 (ABCC1)-mediated resistance to geldanamycins.
OBJECTIVE
Geldanamycin and its analogues belong to a new class of anticancer agents that inhibit the molecular chaperone heat shock protein 90. We hypothesized that membrane transporters expressed on tumor cells may contribute at least in part to cellular sensitivity to these agents. The purpose of this study is to identify novel transporters as determinant for sensitivity and resistance to geldanamycins.


METHODS
To facilitate a systematic study of chemosensitivity across multiple geldanamycin analogues, we correlated mRNA expression profiles of majority of transporters with anticancer drug activities in 60 human tumor cell lines (NCI-60). We subsequently validated the gene-drug correlations using cytotoxicity and transport assays.


RESULTS
The GA analogues displayed negative correlations with mRNA expression levels of the multidrug resistance protein 1 (MRP1, ABCC1). Suppressing MRP1 efflux using the inhibitor MK-571 and small interfering RNA in cell lines with intrinsic and acquired MRP1 overexpression (A549 and HL-60/ADR) and in cell lines stably transduced with MRP1 (MCF7/MRP1) increased intracellular drug accumulation and increased tumor cell sensitivity to geldanamycin analogues.


CONCLUSIONS
These results suggest that elevated expression of MRP1, like the alternative efflux transporter MDR1 (ABCB1, P-glycoprotein), can significantly influence tumor cell sensitivity to geldanamycins as a potential chemoresistance factor.
Pham
Anh-Nhan
AN
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California, 91766, USA.
Wang
Jeffrey
J
Fang
Jialong
J
Gao
Xin
X
Zhang
Yilong
Y
Blower
Paul E
PE
Sadée
Wolfgang
W
Huang
Ying
Y
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000378:metabolism / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics / Q000379:methods; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C059141:verlukast; C421109:multidrug resistance-associated protein 1; C001277:geldanamycin