| Reference | 1. Acta Pharm Sin B. 2014 Jun;4(3):202-7. doi: 10.1016/j.apsb.2014.02.003. Epub 2014
Mar 29.
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PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR.
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Anreddy N(1), Patel A(1), Sodani K(1), Kathawala RJ(1), Chen EP(1), Wurpel JN(1),
Chen ZS(1).
<br>
Author information: <br>
(1)Department of Pharmaceutical Sciences, College of Pharmacy and Health
Sciences, St. John׳s University, Queens, NY 11439, USA.
<br>
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.
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2. Cancer Chemother Pharmacol. 2013 Jul;72(1):189-99. doi:
10.1007/s00280-013-2184-z. Epub 2013 May 15.
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PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in
cancer cells.
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Patel A(1), Tiwari AK, Chufan EE, Sodani K, Anreddy N, Singh S, Ambudkar SV,
Stephani R, Chen ZS.
<br>
Author information: <br>
(1)Department of Pharmaceutical Sciences, College of Pharmacy and Health
Sciences, St. John/’s University, Queens, NY 11439, USA.
<br>
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.<br>
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.<br>
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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3. Cancer Res. 2009 Nov 15;69(22):8645-51. doi: 10.1158/0008-5472.CAN-09-1576. Epub
2009 Nov 10.
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The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung
cancer growth in vitro and in vivo.
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Pardo OE(1), Latigo J, Jeffery RE, Nye E, Poulsom R, Spencer-Dene B, Lemoine NR,
Stamp GW, Aboagye EO, Seckl MJ.
<br>
Author information: <br>
(1)Lung Cancer Biology Group, Cancer Research UK Laboratories, Clinical Sciences
Centre, Hammersmith Hospital Campus of Imperial College London, London, United
Kingdom.
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Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is
initially chemosensitive, but rapidly relapses in a chemoresistant form with an
overall survival of <5%. Consequently, novel therapies are urgently required and
will likely arise from an improved understanding of the disease biology. Our
previous work showed that fibroblast growth factor-2 induces proliferation and
chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth
factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC
proliferation and clonogenic growth in a dose-dependent fashion and prevents
FGF-2-induced chemoresistance. These effects correlate with the inhibition of
both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of
daily oral administration of PD173074 for 28 days in two human SCLC models. In
the H-510 xenograft, tumor growth was impaired similar to that seen with
single-agent cisplatin administration, increasing median survival compared with
control sham-treated animals. Crucially, the effect of cisplatin was
significantly potentiated by coadministration of PD173074. More dramatically, in
H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of
mice. These effects were not a consequence of disrupted tumor vasculature but
instead correlated with increased apoptosis (caspase 3 and cytokeratin 18
cleavage) in excised tumors. Moreover, in vivo imaging with
3/’-deoxy-3/’-[(18)F]fluorothymidine-positron emission tomography ([(18)F]FLT-PET)
showed decreased intratumoral proliferation in live animals treated with the
compound at 7 to 14 days. Our results suggest that clinical trials of FGFR
inhibitors should be undertaken in patients with SCLC and that [(18)F]FLT-PET
imaging could provide early in vivo evidence of response.
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