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Repurposing old carbon monoxide-releasing molecules towards the anti-angiogenic therapy of triple-negative breast cancer

Kourti, Malamati, Westwell, Andrew, Jiang, Wen and Cai, Jun 2019. Repurposing old carbon monoxide-releasing molecules towards the anti-angiogenic therapy of triple-negative breast cancer. Oncotarget 10 (10) , pp. 1132-1148. 10.18632/oncotarget.26638

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Abstract

Triple-negative breast cancer (TNBC) is defined by the lack of expression of the oestrogen and progesterone receptors and HER-2. Recently, carbon monoxide (CO) was found to behave as an important endogenous signalling molecule and to suppress VEGF receptor-2 (VEGFR-2) and protein kinase B phosphorylation. Given that anti-angiogenic drugs exist as one of the few available targeted therapies against TNBC, the aim of this project was to study the effects of CO-releasing molecules (CORMs) on TNBC cell lines and the associated endothelial cells and characterise their anti-angiogenic properties that can be used for the reduction of cancer-driven angiogenesis. Four commercially available CORMs were screened for their cytotoxicity, their effects on cell metabolism, migration, VEGF expression, tube formation and VEGFR-2 activation. The most important result was the reduction in VEGF levels expressed by CORM-treated TNBC cells, along with the inhibition of phosphorylation of VEGFR2 and downstream proteins. The migration and tube formation ability of endothelial cells was also decreased by CORMs, justifying a potential re-purposing of old CORMs towards the anti-angiogenic therapy of TNBC. The additional favourable low cytotoxicity, reduction in the glycolysis levels and downregulation of haem oxygenase-1 in TNBC cells enhance the potential of CORMs against TNBC. In this study, CORM-2 remained the most effective CORM and we propose that CORM-2 may be pursued further as an additional agent in combination with existing anti-angiogenic therapies for a more successful targeting of malignant angiogenesis in TNBC.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Medicine
Publisher: Impact Journals
ISSN: 1949-2553
Date of First Compliant Deposit: 13 February 2019
Date of Acceptance: 22 January 2019
Last Modified: 15 Feb 2019 23:28
URI: http://orca.cf.ac.uk/id/eprint/119478

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