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dc.contributor.advisorBaird, Sarah
dc.contributor.authorPetersen, Jakeb
dc.date.available2019-11-12T22:33:17Z
dc.date.copyright2019
dc.identifier.citationPetersen, J. (2019). Investigation into the Anticancer Mechanism of Action of Novel 4-Substituted Phenylthiazoles and Antihelminthic Benzimidazoles (Thesis, Master of Science). University of Otago. Retrieved from http://hdl.handle.net/10523/9799en
dc.identifier.urihttp://hdl.handle.net/10523/9799
dc.description.abstractRecently, two novel 4-substituted phenylthiazoles, D1 and D2, have been synthesised based upon the marine bacterial secondary metabolite anithiactin A/thiasporine C, and shown to be cytotoxic towards cancer cells below 100 μM, with suggestions of inhibition of tubulin polymerisation. D1 and D2 were then further screened for cytotoxicity in three cancer cell lines (MDA-MB-231, MCF-7, HT-29) and one non-transformed mesenchymal stem-cell line (RCB2157), using the MTT assay. Their effects on the cell cycle and cell death mechanisms were analysed using flow cytometry and fluorescent microscopy and spectroscopy. Unfortunately, no significant changes in cell death mechanisms were observed and previous cytotoxicity results were unable to be replicated. This was attributed to the degradation of the compounds in DMSO solution, likely to cause a loss in biological activity. Antihelminthic benzimidazole drugs mebendazole and albendazole are commonly used to treat a variety of worm infestations in humans. Their mechanism of action against helminths is well-established and involves the inhibition of microtubule formation. Mebendazole has recently shown promising results in pre-clinical in vitro and in vivo cancer studies and is currently in Phase I trials for treatment of glioma. However, the way in which it causes cell death in cancer cells has not been fully explored. Here, the in vitro analysis of the anticancer mechanism of action of mebendazole and a structural analogue albendazole was undertaken. The two drugs were screened for cytotoxicity in three cancer cell lines (MDA-MB-231, MCF-7, HT-29) and one non-transformed mesenchymal stem-cell line (RCB2157), using the MTT assay. Their effects on the cell cycle and cell death mechanisms were analysed using flow cytometry and fluorescent microscopy and spectroscopy. Mebendazole and albendazole were found to selectively kill cancer cells, being most potent in the colorectal cancer cell line HT-29, with IC50 values of 1.3 ± 0.1 μM and 1.4 ± 0.1 μM, respectively. Both mebendazole and albendazole induced caspase-3 activation. Phosphatidylserine exposure, mitochondrial and lysosomal membrane permeability and reactive oxygen species production were all significantly increased compared to control and peaked at 24 hours, with DNA fragmentation increasing in a time-dependent manner peaking at 48 hours. Using Hoechst 33342 staining, nuclear features of apoptosis such as chromatin condensation were found following treatment with both drugs. Cell cycle arrest in the G2/M phase was found, and tubulin structures were significantly altered. Mebendazole and albendazole appear to cause cancer cell death via a mechanism of classical apoptosis and cell cycle arrest, which may originate from the destabilisation of microtubules.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectBenzimidazole
dc.subjectmebendazole
dc.subjectalbendazole
dc.subjectcancer
dc.subjectcell-cycle
dc.titleInvestigation into the Anticancer Mechanism of Action of Novel 4-Substituted Phenylthiazoles and Antihelminthic Benzimidazoles
dc.typeThesis
dc.date.updated2019-11-12T22:02:04Z
dc.language.rfc3066en
thesis.degree.disciplinePharmacology & Toxicology
thesis.degree.nameMaster of Science
thesis.degree.grantorUniversity of Otago
thesis.degree.levelMasters
otago.openaccessOpen
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