PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR.
10.1016/j.apsb.2014.02.003
- Author:
Nagaraju ANREDDY
1
;
Atish PATEL
1
;
Kamlesh SODANI
1
;
Rishil J KATHAWALA
1
;
Eugenie P CHEN
1
;
John N D WURPEL
1
;
Zhe-Sheng CHEN
1
Author Information
1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY 11439, USA.
- Publication Type:Journal Article
- Keywords:
ABC, ATP binding cassette;
ABCC10;
EGFR, epidermal growth factor receptor;
FGFR, fibroblast growth factor receptor;
Fibroblast growth factor receptor;
HEK293, human embryonic kidney 293;
MDR, multidrug resistance;
MRP7, multidrug resistance protein 7;
MSDs, membrane-spanning domains;
Multidrug resistance;
NBDs, nucleotide-binding domains;
NSCLC, non-small cell lung carcinomas;
PD173074;
RTK, receptor tyrosine kinase;
TKI, tyrosine kinase inhibitor;
Tyrosine kinase inhibitor
- From:
Acta Pharmaceutica Sinica B
2014;4(3):202-207
- CountryChina
- Language:English
-
Abstract:
Multidrug resistance protein 7 (MRP7, ABCC10) is a recently identified member of the ATP-binding cassette (ABC) transporter family, which adequately confers resistance to a diverse group of antineoplastic agents, including taxanes, vinca alkaloids and nucleoside analogs among others. Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas (NSCLC) compared to a normal healthy lung tissue. Recent studies revealed increased paclitaxel sensitivity in the Mrp7(-/-) mouse model compared to their wild-type counterparts. This demonstrates that MRP7 is a key contributor in developing drug resistance. Recently our group reported that PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could significantly reverse P-glycoprotein-mediated MDR. However, whether PD173074 can interact with and inhibit other MRP members is unknown. In the present study, we investigated the ability of PD173074 to reverse MRP7-mediated MDR. We found that PD173074, at non-toxic concentration, could significantly increase the cellular sensitivity to MRP7 substrates. Mechanistic studies indicated that PD173074 (1 μmol/L) significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein, thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.
