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01-07-2013 | Original Article

PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells

Authors: Atish Patel, Amit K. Tiwari, Eduardo E. Chufan, Kamlesh Sodani, Nagaraju Anreddy, Satyakam Singh, Suresh V. Ambudkar, Ralph Stephani, Zhe-Sheng Chen

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2013

Abstract

Purpose

Specific tyrosine kinase inhibitors were recently reported to modulate the activity of ABC transporters, leading to an increase in the intracellular concentration of their substrate drugs. In this study, we determine whether PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could reverse ABC transporter-mediated multidrug resistance.

Methods

3-(4,5-Dimethylthiazol-yl)-2,5-diphenyllapatinibrazolium bromide assay was used to determine the effect of PD173074 on reversal of ABC transporter-mediated multidrug resistance (MDR). In addition, [³H]-paclitaxel accumulation/efflux assay, western blotting analysis, ATPase, and photoaffinity labeling assays were done to study the interaction of PD173074 on ABC transporters.

Results

PD173074 significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to substrate anticancer drugs colchicine, paclitaxel, and vincristine. This effect of PD173074 is specific to ABCB1, as no significant interaction was detected with other ABC transporters such as ABCC1 and ABCG2. The observed reversal effect seems to be primarily due to the decreased active efflux of [³H]-paclitaxel in ABCB1 overexpressing cells observed in efflux assay. In addition, no significant change in the ABCB1 expression was observed when ABCB1 overexpressing cells were exposed to 5 μM PD173074 for up to 3 days, thereby further suggesting its role in modulating the function of the transporter. In addition, PD173074 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Interestingly, PD173074 did not inhibit photolabeling of ABCB1 with [¹²⁵I]-iodoarylazidoprazosin (IAAP), showing that it binds at a site different from that of IAAP in the drug-binding pocket.

Conclusions

Here, we report for the first time, PD173074, an inhibitor of the FGFR, to selectively reverse ABCB1 transporter-mediated MDR by directly blocking the efflux function of the transporter.

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Title: PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells
Authors: Atish Patel
Amit K. Tiwari
Eduardo E. Chufan
Kamlesh Sodani
Nagaraju Anreddy
Satyakam Singh
Suresh V. Ambudkar
Ralph Stephani
Zhe-Sheng Chen
Publication date: 01-07-2013
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2184-z

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