title: PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY 11439, USA.
authors.forename: Nagaraju
authors.initials: N
authors.lastname: Anreddy
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY 11439, USA.
authors.forename: Atish
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY 11439, USA.
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Sodani
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY 11439, USA.
authors.forename: Rishil J
authors.initials: RJ
authors.lastname: Kathawala
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY 11439, USA.
authors.forename: Eugenie P
authors.initials: EP
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY 11439, USA.
authors.forename: John N D
authors.initials: JN
authors.lastname: Wurpel
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY 11439, USA.
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
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