Narciclasine, an accessible natural product as a lead compound for new treatments for glioma

Dummer, Benjamin 2022. Narciclasine, an accessible natural product as a lead compound for new treatments for glioma. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Glioblastoma (GBM) is the most deadly and aggressive brain tumour in adults. Despite all current treatment paradigms, they come with a universally poor prognosis and a five-year survival rate of approximately 5%. GBMs are characterised by their highly aggressive and heterogeneous nature as well as their ability to invade the surrounding parenchyma and resist chemoradiotherapy. Tumour recurrence is an inescapable fact of GBM biology, and a causal relationship has been attributed in part to a small subpopulation of self-renewing and tumorigenic cancer stem cells (CSC). CSC do not operate in isolation but rather they function as part of an active ecosystem from where they are able to affect their microenvironment through cues from their niches. Despite the best efforts of clinicians and researchers, GBM survival rates have been consistent for decades. New drug therapies have failed to make inroads into this devastating disease partly due to their inability to cross the blood brain barrier (BBB). With such poor outcomes, new therapies are vital in the hope of combating this disease and natural products offer a promising option to develop preclinical candidates. The natural product narciclasine (NAR) from the Amaryllidaceae (amaryllis) family has been shown to have a potent anti-glioma effect and has the potential to be a promising pre-clinical candidate. Therefore, we established a novel NAR extraction method involving solvent partitions from which we could obtain pure forms of NAR in large quantities. We assessed our extracted NAR potency against three human primary cell lines and identified that it has a potent effect against GBM cells in vitro in the low nanomolar range. Cell viability studies on FACS sorted GBM subpopulations of stem and nonstem cells found no difference in treatment response across two human primary cell lines. We developed and novel niacin pro-drug which maintained similar levels of potency whilst being optimised for intranasal administration, bypassing the BBB. We conducted a proof of concept in vivo intranasal delivery study to determine if NAR is a viable candidate for this method of administration. However, we were unable to detect NAR, likely due to insufficient dosages.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Pharmacy
Subjects:	Q Science > Q Science (General)
Funders:	KESS2
Date of First Compliant Deposit:	11 January 2023
Last Modified:	06 Jan 2024 04:41
URI:	https://orca.cardiff.ac.uk/id/eprint/155645

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