The stimulation of A3 adenosine receptors reduces bone-residing breast cancer in a rat preclinical model

Katia Varani, Fabrizio Vincenzi, Martina Targa, Beatrice Paradiso, Annapaola Parrilli, Milena Fini, Giovanni Lanza, Pier Andrea Borea

Research output: Contribution to journalArticlepeer-review

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. A3 adenosine receptor (A3AR) 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 A3ARs in tumour-related signalling pathway, A3AR expression and functional role were analysed in MRMT-1 cells. The effect of chronic treatment with an A3AR 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. A3ARs 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 A3AR stimulation to partially reduce tumour progression. Our findings highlighted the effectiveness of A3AR stimulation in the inhibition of breast tumour-derived bone metastasis growth strongly suggesting that targeting A 3ARs may have promising therapeutic value in the treatment of bone-residing breast cancer.

Original languageEnglish
Pages (from-to)482-491
Number of pages10
JournalEuropean Journal of Cancer
Volume49
Issue number2
DOIs
Publication statusPublished - Jan 2013

Keywords

  • A adenosine receptors
  • Bone-residing breast cancer
  • Cl-IB-MECA
  • MRMT-1 cells
  • Rat tibia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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