The stimulation of A(3) adenosine receptors reduces bone-residing breast cancer in a rat preclinical model

Abstract

Amongst cancers with poor prognosis those originating from breast commonly metastasise to the skeleton for the high affinity of breast cancer cells to bone. A(3) adenosine receptor (A(3)AR) agonists were found to be potent anti-tumour agents even if their effect on bone-residing breast cancer has not yet been investigated. An animal model of surgery-induced metastasis was used to mimic the human condition in an attempt to develop a novel effective treatment strategy. Sprague-Dawley rats receiving intra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells developed cancer-associated osteolytic lesions and structural damage that were monitored by microcomputed tomography imaging and histological analysis. To address the involvement of A(3)ARs in tumour-related signalling pathway, A(3)AR expression and functional role were analysed in MRMT-1 cells. The effect of chronic treatment with an A(3)AR agonist, 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyl-uronamide (Cl-IB-MECA) in comparison with cisplatin, was evaluated on rat tumour growth and bone cancer pain. A(3)ARs were expressed in MRMT-1 cells and their activation reduced NF-kB, increased p53 expression and apoptosis, inhibited tumour cell proliferation and migration. In vivo Cl-IB-MECA administration, started on day 1 after tumour cell injection, produced a significant reduction in tumour growth and cancer pain. Cl-IB-MECA treatment, performed on days 5 and 10 after the tumour cell inoculation, revealed the capability of A(3)AR stimulation to partially reduce tumour progression. Our findings highlighted the effectiveness of A(3)AR stimulation in the inhibition of breast tumour-derived bone metastasis growth strongly suggesting that targeting A(3)ARs may have promising therapeutic value in the treatment of bone-residing breast cancer.