Investigation of the effects of adenosine and purine nucleoside analogues on the viability of human breast cancer cells

Henson, Alexander David 2010. Investigation of the effects of adenosine and purine nucleoside analogues on the viability of human breast cancer cells. PhD Thesis, Cardiff University.

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Abstract

Breast cancer is the second leading cause of cancer death in women in the UK and so there is a need to develop new treatments for this. The aims of these studies were to investigate the effects of adenosine receptor agonists and antagonists, the endogenous compounds adenosine and 2 ’-deoxyadenosine and the clinically used purine nucleoside analogues on the viability of breast cancer cells in vitro. Initial studies identified the expression of all four adenosine receptors in the MCF-7 (ER-positive) and MDAMB231 (ER-negative) breast cancer cell lines but these receptors were not involved per se in maintaining cell viability. Adenosine and 2’-deoxyadenosine were able to reduce cell viability by mechanisms involving adenosine receptor activation in the MCF-7 cells, a reduction in extracellular regulated kinase 1/2 (ERK 1/2) phosphorylation in the MDAMB231 cells and intracellular phosphorylation by adenosine kinase in both cell lines. Further studies identified that the clinically used 2’-deoxyadenosine analogue, clofarabine, had equal potency in the ER-negative cell lines compared to a leukaemia cell line in vitro. The ER-positive cells were 8 - fold more resistant to clofarabine, however. Inhibition of ribonucleotide reductase appeared to be the primary mechanism of action of clofarabine and cladribine, but not fludarabine in the MCF-7 and MDAMB231 cell lines. ERK 1/2 signalling was also partly required for the action of clofarabine in the MDAMB231, but not the MCF-7 cells. Studies on the resistance of clofarabine in ER-positive cells identified that increased basal expression of the metabolising enzyme, cytostolic 5’-nucleotidase II and the ribonucleotide reductase subunit, p53R2, were correlated with decreased sensitivity to clofarabine. Drug-induced p53R2 expression in p53 wild-type MCF-7 cells also contributed to resistance. The present study highlights the potential for clofarabine as a treatment for breast cancers, particularly ER-negative cancers where patients have a very poor prognosis.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit:	30 March 2016
Last Modified:	10 Jan 2018 02:47
URI:	https://orca.cardiff.ac.uk/id/eprint/55465

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