Perhexiline as a Potential Treatment for Colorectal Cancer
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(Thesis)
Date
2022
Authors
Dhakal, Bimala
Editors
Advisors
Maddern, Guy
Drew, Paul
Fenix, Kevin
Drew, Paul
Fenix, Kevin
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Thesis
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Abstract
This thesis describes studies investigating the potential to repurpose the cardiac drug perhexiline as a novel drug for the management of colorectal cancer (CRC). CRC is commonly diagnosed and is a leading cause of cancer-related death worldwide. Despite improvements in prevention and treatment, the global burden of CRC continues to rise. About 50% of patients present with, or will develop, metastatic disease, which remains a relatively lethal disease. New treatment strategies are required. Perhexiline is used clinically for some cardiac conditions. It is reported to inhibit carnitine palmitoyltransferase-1 (CPT1), essential for mitochondrial uptake of longchain fatty acids. This reduces fatty acid metabolism, increases glucose metabolism and ATP production, and so increases myocardial efficiency. There are two major influences on the growth of a cancer - changes within the cancer cell itself, and changes in the tumour microenvironment (TME). The in vitro effect of perhexiline on CRC cancer cells and macrophages, an important cell in the TME, is studied in this thesis. Fatty acid oxidation is commonly increased in cancer cells, so perhexiline might be expected to affect their viability. In Chapter 2 the published literature is reviewed, showing that perhexiline reduces the viability of numerous cancer cell types, but there are no studies focused solely on CRC cells. Chapter 3 is a published paper showing for the first time that perhexiline reduces the viability of CRC cell lines, grown as monolayers or spheroids, or patient-derived CRC organoids. Some of the literature reviewed in Chapter 2 suggested that the mechanisms of action of perhexiline may not just be restricted to inhibition of CPT1. In silico binding and docking studies described in Chapter 4 show that perhexiline has the potential to interact with many other molecular targets. Analysis of publicly available gene expression datasets are consistent with perhexiline acting on more targets than just CPT1. The TME consist of non-cancer cells and the matrix within which the cells are embedded. Macrophages are commonly present in the TME. They can reversibly alter their phenotype in response to environmental stimuli, and either inhibit or promote tumorigenesis (M1 and M2 macrophages respectively). Reprogramming of M2 macrophages into M1 macrophages by small molecule compounds may have novel therapeutic potential. In the studies reported in Chapter 5, the in vitro differentiation of M1 and M2 macrophages from THP-1 monocytes in the presence of perhexiline was studied. The drug promoted the expression of M1 markers and inhibited the expression of M2 markers. Mass spectrometry studies of drug treated cells confirmed that perhexiline promoted the M1 macrophage phenotype and identified protein changes induced by the drug. The studies reported here provide new insights into the potential for perhexiline to directly inhibit the viability of CRC cancer cells and to modify tumour associated macrophages to a tumour repressive phenotype. They broaden the understanding of the mechanisms of action of this drug. They provide a sound basis for further investigation into the possible repurposing of perhexiline as a novel therapeutic for the clinical management of CRC and other cancers.
School/Discipline
Adelaide Medical School
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2022
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This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals