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

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.

• Authors: Atish Patel, Amit K Tiwari, Eduardo E Chufan, Kamlesh Sodani, Nagaraju Anreddy, Satyakam Singh, Suresh V Ambudkar, Ralph Stephani, Zhe-Sheng Chen
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 72 Issue 1 Pg. 189-99 (Jul 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23673445 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Affinity Labels
• Antineoplastic Agents
• Neoplasm Proteins
• PD 173074
• Protein Kinase Inhibitors
• Pyrimidines
• Receptors, Fibroblast Growth Factor
• Recombinant Proteins
• Tubulin Modulators
• Vincristine
• Adenosine Triphosphate
• Paclitaxel
• Colchicine

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (agonists, antagonists & inhibitors, genetics, metabolism)
• Adenosine Triphosphate (metabolism)
• Affinity Labels (pharmacology)
• Allosteric Regulation
• Antineoplastic Agents (agonists, metabolism, pharmacology)
• Biological Transport (drug effects)
• Cell Line, Tumor
• Colchicine (agonists, pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• HEK293 Cells
• Humans
• Hydrolysis (drug effects)
• Neoplasm Proteins (agonists, antagonists & inhibitors, metabolism)
• Neoplasms (drug therapy, enzymology, metabolism)
• Paclitaxel (agonists, metabolism, pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors)
• Recombinant Proteins (agonists, antagonists & inhibitors, metabolism)
• Tubulin Modulators (agonists, metabolism, pharmacology)
• Vincristine (agonists, pharmacology)