Colorectal cancer (CRC) is the third most widespread and fourth most fatal
malignancy disease. The CRC from a primary site can spread to other tissues,
forming secondary tumours. CRC can metastasise to the liver through the effect
of K-Ras and Pten mutation (Mt.) (Abbas et al. 2020). This study aimed to assess
the hypothesis that the Ran inhibitor mebendazole MBZ reduces cell invasion
and metastasis of CRC. I have investigated MBZ effect on the CRC isogenic
human cell lines with specific mutations (HCT-116 K-Ras, DLD-1 K-Ras and Pten
deletion and wild type HCT-116 and DKO-3. I used qRT-PCR and western
blotting to identify expression levels of various genes and signalling molecules
after treatment with 0.5 mM MBZ. In addition, several assays were performed to
investigate MBZ effect on biological properties of the cells such as proliferation,
migration, invasion, and colony formation. MBZ downregulated Ran and induced
apoptosis through inhibition of Bcl-2 expression as well as inducing caspase -3,
-7, -9 and PARP cleavage. Moreover, MBZ showed an effect on immune
response by down regulating C5a, IL-1ß and IL-1α analysed at mRNA level.
When treated with MBZ, the migration, invasion and colony formation abilities of
HCT-116 K-Ras Mt., DLD-1 K-Ras Mt. and HCT-116 Pten-/- were significantly
reduced compared to a control treated cell line. This was also the case with wild type cell lines such as HCT-116 and DKO-3. Furthermore, signalling molecules
such as p- Erk 1/2 and p- Akt were upregulated after MBZ treatment and exert
inhibition on Akt 1/2/3 and VEGFR1/2 mRNA levels. In conclusion; MBZ which is
a Ran inhibitor, has significantly reduced proliferation, colony formation, and
migration in colorectal cell lines with K-Ras and Pten gene deletion compared to
wild type cells in a dose-dependent manner. This work paves the way to clinical
validation of MBZ as a combination therapy for reducing the invasion of CRC
cells.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/19110 |
| Date | January 2020 |
| Creators | Elrewey, Hussein A.S. |
| Contributors | McLean, Samantha, Kantamneni, Sriharsha, El-Tanani, Mohamed, Morgan, Richard |
| Publisher | University of Bradford, Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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