Affiliation:
1. Department of Internal Medicine, Oncology Division, Faculty of Health Sciences, University of the Witwatersrand, 7
York Road, Parktown, Johannesburg, 2193, Republic of South Africa (RSA)
Abstract
<p>Background: The Hedgehog (HH) pathway is a key regulator of many important processes
in vertebrate embryonic development, including stem cell maintenance, cell differentiation, tissue
polarity and cell proliferation. During pathway activation, Ptch no longer inhibits Smo and the full
length Gli translocates to the nucleus resulting in the transcription of oncogenes. When constitutively
activated, this leads to tumorigenesis in several human cancers. Cyclopamine acts as an antagonist of
the HH signalling pathway by directly binding to the Smo heptahelical domain. The involvement of
this pathway in metastasis, and its presence in cancer stem cells (CSCs), makes it a valid option for
developing a targeted therapeutic against it.
<p>
Methods: CSC were isolated from DLD1 and HT29 cell lines using magnetic cell separation labelling
the CD133 receptor. The growth patterns of isolated CSCs (CD133 positive) in comparison to
non-stem cells (CD133 negative) were analysed using real-time cell impedance assays (RTCA).
Thereafter, adhesion, invasion and migration assays were performed with the application of small
molecule inhibitors. The expression levels of CD133 and SHH were evaluated using confocal microscopy
following treatment with cyclopamine.
<p>
Results and Discussion: Growth of CSCs appeared to be slower than non-CSCs. Adhesion, invasion
and cell migration were inhibited when CSCs were pharmacologically treated either with cyclopamine
or SANT-2 (a synthetic analogue of cyclopamine), small molecule inhibitors of the HH pathway.
Using confocal microscopy the cell surface expression of Sonic Hedgehog (SHH) was significantly
decreased following treatment with cyclopamine, while the expression of CD133 remained
unaffected.
<p>
Conclusion: Considering these in vitro results, small molecule inhibitors targeting the SHH pathway
appear to be promising therapeutic tools for the treatment of metastatic colon CSCs.</p>
Publisher
Bentham Science Publishers Ltd.
Subject
Cancer Research,Oncology,Molecular Medicine
Cited by
1 articles.
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