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.
Highlights
Cancer deriving from the mammary gland affects more than 1.3 million women worldwide each year, with more than 55,000 reported cases in the U.K. in 2015 (Cancer Research UK)
Given that anti-angiogenic drugs exist as one of the few available targeted therapies against triple-negative breast cancer (TNBC), the aim of this project was to study the effects of carbon monoxide (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
Vascular endothelial cells (ECs) around the tumour area should express effective VEGFRs (RTKs) that upon binding with vascular endothelial growth factor (VEGF) will initiate the proangiogenic signal through activation of their downstream signalling pathways
Summary
Cancer deriving from the mammary gland (breast cancer) affects more than 1.3 million women worldwide each year, with more than 55,000 reported cases in the U.K. in 2015 (Cancer Research UK). Clinical data reveal that approximately 15% of all breast cancers are diagnosed as TNBC, which occurs more frequently among minority (black race, Hispanic ethnicity) and younger women (
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