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Combining carbon monoxide-releasing molecules with anti-VEGF therapy for triple-negative breast cancer therapy

Kourti, Malamati 2018. Combining carbon monoxide-releasing molecules with anti-VEGF therapy for triple-negative breast cancer therapy. PhD Thesis, Cardiff University.
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Abstract

Triple-negative breast cancer (TNBC) is defined by the lack of expression of the oestrogen and progesterone receptors and the overexpression of HER-2. Recently, carbon monoxide (CO) was found to behave as an important endogenous signalling molecule and interestingly, to suppress vascular endothelial growth factor receptor-2 (VEGFR2) and protein kinase B (AKT) phosphorylation. Given that anti-angiogenic drugs exist as one of the few available therapies against TNBC, CO-releasing molecules (CORMs) could be used as part of a combination therapy, in order to reduce cancerdriven angiogenesis. Therefore, the aim of this project was to study any potential antiangiogenic properties of four commercially available CORMs and after the selection and structural modification of one of them, new analogues would be synthesized and evaluated in vitro. The four commercially available CORMs were screened for cytotoxicity against TNBC, epithelial and endothelial cells and found to be moderately toxic. They were also shown to reduce the glycolytic metabolism of TNBC cells, decrease VEGF excretion from both TNBC cell lines tested and downregulate the expression of the cytoprotective enzyme haem oxygenase-1 (HO-1). They were finally reported to moderately inhibit the activation of VEGFR2 and other downstream proteins upon stimulation with VEGF and reduce the tube formation ability of endothelial cells. These results were crucial for the selection of one lead compound, which was subjected to structural modifications and 15 new analogues were produced. The new molecules showed a more favourable cytotoxicity profile, with two of them being selectively toxic against TNBC. All the 15 analogues retained the ability to reduce VEGF excretion from TNBC cells and two of them were chosen for further studies. These two complexes downregulated the expression of HO-1 at similar levels and reduced the phosphorylation of some VEGFR2 downstream proteins more than the parent compound. Finally, both CORMs decreased the tube formation activity of endothelial cells. In summary, two of the commercially available and two of the newly synthesized CORMs showed promising anti-angiogenic properties and should be pursued further, in order to identify a mechanism of action for these organometallic complexes.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 9 November 2018
Last Modified: 09 Nov 2018 11:49
URI: http://orca-mwe.cf.ac.uk/id/eprint/116563

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