title: Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth.
abstract: Recently it has become clear that the cost associated with the Warburg effect, which is inefficient production of ATP, is offset by selective advantages that are produced by resultant intracellular metabolic alterations. In fact tumors may be addicted to the Warburg effect. In addition these alterations result in changes in the extracellular tumor microenvironment that can also produce selective advantages for tumor cell growth and survival. One such extracellular alteration is increased adenosine concentrations that have been shown to impair T cell mediated rejection and support angiogenesis. The expression of the A2A receptor in non-small cell cancer (NSCLC) tissues, cell lines and cancer associated fibroblasts (CAF) was determined by performing immunohistrochemistry and immunoblot analysis. The efficacy of the A2A receptor antagonists in vivo was evaluated in a PC9 xenograft model. To determine the mode of cell death induced by A2A receptor antagonists flow cytometry, immunoblot, and cytotoxic analysis were performed. We found that a significant number of lung adenocarcinomas express adenosine A2A receptors. Antagonism of these receptors impaired CAF and tumor cell growth in vitro and inhibited human tumor xenograft growth in mice. These observations add to the rationale for testing adenosine A2A receptor antagonists as anticancer therapeutics. Not only could there be prevention of negative signaling in T cells within the tumor microenvironment and inhibition of angiogenesis, but also an inhibitory effect on tumor-promoting, immunosuppressive CAFs and a direct inhibitory effect on the tumor cells themselves.
authors.affiliation: Department of Immunology; H. Lee Moffitt Cancer Center; Tampa, FL USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Mediavilla-Varela
authors.affiliation: Department of Immunology; H. Lee Moffitt Cancer Center; Tampa, FL USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Luddy
authors.affiliation: Department of Immunology; H. Lee Moffitt Cancer Center; Tampa, FL USA.
authors.forename: David
authors.initials: D
authors.lastname: Noyes
authors.affiliation: Anatomic Pathology Department; H. Lee Moffitt Cancer Center; Tampa, FL USA.
authors.forename: Farah K
authors.initials: FK
authors.lastname: Khalil
authors.affiliation: Translational Research Core; Clinical Pharmacology Lab; H. Lee Moffitt Cancer Center; Tampa, FL USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Neuger
authors.affiliation: Department of Women's Oncology and Experimental Therapeutics; H. Lee Moffitt Cancer Center; Tampa, FL USA.
authors.forename: Hatem
authors.initials: H
authors.lastname: Soliman
authors.affiliation: Department of Immunology; H. Lee Moffitt Cancer Center; Tampa, FL USA; Thoracic Oncology Department; H. Lee Moffitt Cancer Center; Tampa, FL USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Antonia
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008819:Mice, Nude; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385
keywords: NSCLC; SCH58261; ZM241385; adenosine A2A receptor; cancer associated fibroblasts; cell death; tumor microenvironment
references.citation: Mol Vis. 2012;18:1010-20
references.pmid: 22550395
references.citation: Anesthesiology. 2012 Jan;116(1):159-69
references.pmid: 22126917
references.citation: Transplant Proc. 2001 Nov-Dec;33(7-8):3816-8
references.pmid: 11750625
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1547-52
references.pmid: 20080644
references.citation: Cancer Res. 1999 Oct 1;59(19):5002-11
references.pmid: 10519415
references.citation: Am J Pathol. 2008 Jun;172(6):1675-82
references.pmid: 18467695
references.citation: Expert Opin Pharmacother. 2012 Jan;13(1):111-4
references.pmid: 22149371
references.citation: Am J Respir Cell Mol Biol. 2009 Mar;40(3):251-9
references.pmid: 18703794
references.citation: PLoS One. 2012;7(10):e44368
references.pmid: 23144692
references.citation: Cancer Res. 2012 May 1;72(9):2190-6
references.pmid: 22396496
references.citation: Am J Pathol. 2004 Jun;164(6):1887-92
references.pmid: 15161625
references.citation: Int J Oncol. 2011 Mar;38(3):655-63
references.pmid: 21240461
references.citation: Cancer Cell. 2010 Feb 17;17(2):135-47
references.pmid: 20138012
references.citation: Synapse. 2012 Feb;66(2):95-105
references.pmid: 21905127
references.citation: Transplantation. 2009 Aug 15;88(3):330-8
references.pmid: 19667934
references.citation: Oncogene. 2003 Nov 20;22(52):8487-97
references.pmid: 14627989
references.citation: Oncogene. 2010 Sep 30;29(39):5346-58
references.pmid: 20661219
references.citation: Mol Biol Cell. 2007 Jan;18(1):14-23
references.pmid: 17065555
references.citation: Purinergic Signal. 2013 Jun;9(2):215-26
references.pmid: 23179048
references.citation: Cell Death Differ. 2007 Jul;14(7):1315-23
references.pmid: 17396131
references.citation: Clin Exp Pharmacol Physiol. 2009 Oct;36(10):963-8
references.pmid: 19413596
references.citation: Handb Exp Pharmacol. 2009;(193):399-441
references.pmid: 19639290
references.citation: J Thorac Oncol. 2011 Jan;6(1):209-17
references.pmid: 21107292
references.citation: Curr Opin Genet Dev. 2009 Feb;19(1):67-73
references.pmid: 19211240
references.citation: Nat Rev Cancer. 2011 Feb;11(2):85-95
references.pmid: 21258394
references.citation: Mol Pharmacol. 2005 May;67(5):1406-13
references.pmid: 15673602
references.citation: J Cell Mol Med. 2011 Mar;15(3):635-46
references.pmid: 20184663
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13132-7
references.pmid: 16916931
references.citation: Science. 2010 Nov 5;330(6005):827-30
references.pmid: 21051638
references.citation: BMC Pulm Med. 2012 Jun 13;12:24
references.pmid: 22694981
references.citation: BMC Biol. 2010 Jun 25;8:88
references.pmid: 20598111
references.citation: Br J Cancer. 2008 Nov 4;99(9):1375-9
references.pmid: 18797460
references.citation: Biochim Biophys Acta. 2011 May;1808(5):1400-12
references.pmid: 20888788
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10684-9
references.pmid: 19541651
references.citation: Cancer Res. 2010 Mar 15;70(6):2245-55
references.pmid: 20179192
references.citation: F1000 Biol Rep. 2011;3:21
references.pmid: 22003368