ACS Medicinal Chemistry Letters
Letter
cancer cell lines.25 Furthermore, significant levels of hERG
channel expression have been found in a variety of other tumor
cell lines including epithelial, neuronal, and leukemic cells.12
Because hERG is expressed in tumor tissue and is absent in
normal tissue, hERG may be regarded as a potential biomarker
for tumors. Accordingly, the imaging of hERG channels could
provide useful information for tumor detection and labeling.
Because of the high levels of hERG expression in colorectal
cancer cells (HT-29 cells), the potential of the synthesized
probes 1a−1c in tumor cell imaging was evaluated using HT-29
demonstrated that these probes are able to label hERG
channels for visualization. When 100 μM of astemizole, a high-
affinity inhibitor, was delivered into the HT-29 cells, the
fluorescence intensity observed was quenched (Figure 3),
indicating that these probes can be used as a labeling toolkit for
hERG highly expressing tumor cells. In addition, hERG channel
blockers were found to induce apoptosis and produce
antiproliferative effects in tumor cells by directly blocking the
hERG channels, and thus play a role in anticancer therapy.12
Cisapride has been confirmed to prevent gastric cancer cell
proliferation by inhibition of hERG channels.26 Thus, the
hERG channels could be used not only as a tumor biomarker
but also as a future drug target. Small-molecule fluorescent
probes have been used for drug screening in recent years.
Therefore, we expect that these fluorescent probes for hERG
channels could be employed as competitive substrates for
hERG inhibitor activity screening and applied in the detection
of tumors. Based on these preliminary results, our laboratory
will pursue the further development of fluorescent probes for
hERG channels.
In conclusion, three small-molecule fluorescent probes, with
excellent fluorescent properties for hERG channel localization
and visualization, have been designed and synthesized. The
probes have been successfully used to label the hERG channels
in hERG-transfected HEK293 (hERG-HEK293) cells and
human colorectal cancer (HT-29) cells at the micromolar
level. Moreover, these probes exhibited high inhibitory activity
on the hERG channels and acceptable toxicity in cells. The
preparation of these small fluorescent probes is also convenient.
These features make the probes favorable for drug screening
and cell staining. Therefore, these probes are anticipated to be
applied in the detection of hERG channels, as well as in
physiological and pathological studies of hERG channels.
Funding
The present project was supported by grants from the National
Natural Science Foundation of China (No. 30901836), the
Doctoral Fund of Shandong Province (No. BS2012YY008), the
Shandong Natural Science Foundation (No. JQ201019), the
Scientific Research Foundation for the Returned Overseas
Chinese Scholars, and the Fundamental Research Funds of
Shandong University (Nos. 2009TB021 and 2012JC002). We
also thank Professor Gui-Rong Li from the University of Hong
Kong for his generous gift of the hERG-transfected HEK293
cells. Our cell imaging work was performed at the Microscopy
Characterization Facility, Shandong University.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
hERG, human ether-a-go-go-related gene; LQTS, long QT
syndrome; hERG-HEK293 cells, hERG transfected HEK293
cells
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
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expression-related chemosensitivity in cancer cells and its modulation
by erythromycin. Cancer Chemother. Pharmacol. 2005, 56, 212−220.
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Full experimental procedures; analytical and spectral
characterization data of all compounds (PDF)
AUTHOR INFORMATION
■
(13) Babcock, J. J.; Li, M. hERG channel function: beyond long QT.
Acta Pharmacol. Sin. 2013, 34, 329−335.
Corresponding Author
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strategies in fluorescent probe development. Chem. Rev. 2012, 112,
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Author Contributions
The manuscript was written through the contributions of all
authors. All authors have given approval to the final version of
the manuscript.
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labeling technology in live cell studies: probe-design concepts and
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