The effect of adenosine A1 receptor agonist and antagonist on p53 and caspase 3, 8, and 9 expression and apoptosis rate in MCF-7 breast cancer cell line

Mehdi Nikbakht Dastjerdi, Mohammad Zamani Rarani, Ali Valiani, Mohsen Mahmoudieh


Adenosine receptor family especially A1 type is expressed in breast cancer cells in which P53 and caspase genes are wild-type. The aim of this study was to investigate the correlation between A1 receptor and either cell apoptosis or proliferation and also to recognize the relationship between this receptor and P53 and the expression of caspases 3, 8 and 9 in MCF-7 cell line. MCF-7 cells were treated intermittently with A1 receptor agonist N6-Cyclopentyladenosine (CPA) and A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) in different times to measure the expression of p53, caspase 3, 8 and 9 besides apoptosis and survival rate. Our findings indicated that DPCPX significantly induced apoptosis in MCF-7 cells while the cell viability was reduced specially 72 h after the treatment and the expression of p53 gene and caspase expressions was dramatically up-regulated. On the other hand, CPA increased the cell viability and reduced apoptosis in MCF-7 cells. Our results indicated a significant down-regulation in the MCF-7 mRNA expression of p53 and caspases 3, 8 and 9. Furthermore, DPCPX induced p53 and caspase 3, 8 and 9 expressions that consequently promotes the cell apoptosis in MCF‑7 cells. Therefore, DPCPX can be considered as an anti-cancer drug.


Caspase; Adenosine A1; Apoptosis; Genes; p53; MCF-7 cells

Full Text:



World Health Organization (W.H.O.) Fact sheet N 297 February 2015. Available at:,oct 9,2015.

American Cancer Society. Overview: Breast cancer 2015. Available at:, oct 12,2015.

Holliday DL, Speirs V. Choosing the right cell line for breast cancer research. Breast Cancer Res. 2011;13:215.

Tripodo G, Mandracchia D, Collina S, Rui M, Rossi D. New perspectives in cancer therapy: the biotin-antitumor molecule conjugates. Med Chem. 2014;8:1-4.

Rosenberg SA. Finding suitable targets is the major obstacle to cancer gene therapy.Cancer Gene Ther. 2014;21:45-47.

Williams M, Jarvis MF. Purinergic and pyrimidinergic receptors as potential drug targets.BiochemPharmacol. 2000;59:1173-1185.

Burnstock G. Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol Rev. 2006;58:58-86.

Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci. 2007;64:1471-1483.

Merighi S, Mirandola P, Varani K, Gessi S, Leung E, Baraldi PG, et al. A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol Ther. 2003;100:31-48.

Rastogi RP, Richa, Sinha RP. Apoptosis: molecular mechanisms and pathogenicity. 2009;8:155-181.

Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene. 2003;22:9030-9040.

Jain M, Kasetty S, Khan S, Desai A. An insight to apoptosis. J Res Prac Dent. 2014:ID 372284.

Jin Z, Wallace L, Harper SQ, Yang J. PP2A: B56ϵ, a substrate of caspase-3, regulates p53-dependent and p53-independent apoptosis during development. J Biol Chem. 2010;285:34493-34502.

Su Z, Yang Z, Xu Y, Chen Y, Yu Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer. 2015;14:48.

Li J, Yuan J. Caspases in apoptosis and beyond. Oncogene. 2008;27:6194-6206.

Hermeking H. MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer. 2012;12:613-626.

Zhang A, Xu M, Mo YY. Role of the lncRNA–p53 regulatory network in cancer. J Mol Cell Biol. 2014;6:181-191.

Miyake N, Chikumi H, Takata M, Nakamoto M, Igishi T, Shimizu E. Rapamycin induces p53-independent apoptosis through the mitochondrial pathway in non-small cell lung cancer cells. Oncol Rep. 2012;28:848-854.

Suzuki K, Matsubara H. Recent advances in p53 research and cancer treatment. J Biomed Biotechnol. 2011:ID 978312.

Mirza A, Basso A, Black S, Malkowski M, Kwee L, Patcher JA, et al. RNA interference targeting of A1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis. Cancer Biol Ther. 2005;4:1355-1360.

Lin Zh, Yin P, Reierstad S, O’Halloran M, Coon V JS, Pearson EK, et al. Adenosine A1 receptor, a target and regulator of ERα action, mediates the proliferative effects of estradiol in breast cancer. Oncogene. 2010;8:1114–1122.

AghaeiM, PanjehpourM,Karami-TehraniF,Salami S. Molecular mechanisms of A3 adenosine receptor-induced G1 cell cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines: involvement of intrinsic pathway. J Cancer Res Clin Oncol. 2011;137:1511–1523.

Lee HT, Gallos G, Nasr SH, Emala CW. A1 adenosine receptor activation inhibits inflammation, necrosis, and apoptosis after renal ischemia-reperfusion injury in mice. J Am Soc Nephrol. 2004;15:102–111.

Turner CP, Blackburn MR, Rivkees SA. A1 adenosine receptors mediate hypoglycemia-induced neuronal injury. J Mol Endocrinol. 2004;32:129–144.

Selim ME, Hendi AA. Gold nanoparticles induce apoptosis in MCF7 human breast cancer cells. Asian Pac J Cancer Prev. 2012;13:1617-1620.

Gerber DE. Targeted therapies: a new generation of cancer treatments. Am Fam Physician. 2008;77: 311-319.

Aghaei M, Shirali S. A3 adenosine receptor agonist (IB-MECA) induced apoptosis in OVCAR3 ovary cancer cell line. Res Pharm Sci. 2012;7:S97.

Hosseinzadeh H, Jafari MR, Shamsara J. Selective inhibitory effect of adenosine A1 receptor agonists on the proliferation of human tumor cell lines. Iran Biomed J. 2008;12:203-208.

Sai K, Yang D, Yamamoto H, Fujikawa H, Yamamoto S, Nagata T, et al. A1 adenosine receptor signal and AMPK involving caspase-9/-3 activation are responsible for adenosine-induced RCR-1 astrocytoma cell death. Neurotoxicology. 2006;27:458-467.

OtsukiT,Kanno T, Fujita Y, Tabata C, Fukuoka K, Nakano T, et al. A3 adenosine receptor-mediated p53-dependent apoptosis in Lu-65 human lung cancer cells. Cell Physiol Biochem. 2012;30:210-220.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.