title: Caffeine promotes anti-tumor immune response during tumor initiation: Involvement of the adenosine A2A receptor.
abstract: Epidemiologic studies depict a negative correlation between caffeine consumption and incidence of tumors in humans. The main pharmacological effects of caffeine are mediated by antagonism of the adenosine receptor, A2AR. Here, we examine whether the targeting of A2AR by caffeine plays a role in anti-tumor immunity. In particular, the effects of caffeine are studied in wild-type and A2AR knockout (A2AR(-/-)) mice. Tumor induction was achieved using the carcinogen 3-methylcholanthrene (3-MCA). Alternatively, tumor cells, comprised of 3-MCA-induced transformed cells or B16 melanoma cells, were inoculated into animal footpads. Cytokine release was determined in a mixed lymphocyte tumor reaction (MLTR). According to our findings, caffeine-consuming mice (0.1% in water) developed tumors at a lower rate compared to water-consuming mice (14% vs. 53%, respectively, p=0.0286, n=15/group). Within the caffeine-consuming mice, tumor-free mice displayed signs of autoimmune alopecia and pronounced leukocyte recruitment intocarcinogen injection sites. Similarly, A2AR(-/-) mice exhibited reduced rates of 3-MCA-induced tumors. In tumor inoculation studies, caffeine treatment resulted in inhibition of tumor growth and elevation in proinflammatory cytokine release over water-consuming mice, as depicted by MLTR. Addition of the adenosine receptor agonist, NECA, to MLTR resulted in a sharp decrease in IFNγ levels; this was reversed by the highly selective A2AR antagonist, ZM241385. Thus, immune response modulation through either caffeine or genetic deletion of A2AR leads to a Th1 immune profile and suppression of carcinogen-induced tumorigenesis. Taken together, our data suggest that the use of pharmacologic A2AR antagonists may hold therapeutic potential in diminishing the rate of cancer development.
authors: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address: einyh@post.bgu.ac.il.
authors: Hadar
authors: H
authors: Eini
authors: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address: fischman@bgu.ac.il.
authors: Valeria
authors: V
authors: Frishman
authors: Department of Nephrology, Soroka Medical Center Beer-Sheva, Israel. Electronic address: roberty@clalit.org.il.
authors: Robert
authors: R
authors: Yulzari
authors: Department of Pathology, Soroka Medical Center Beer-Sheva, Israel. Electronic address: leonidka@clalit.org.il.
authors: Leonid
authors: L
authors: Kachko
authors: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address: lewis@bgu.ac.il.
authors: Eli C
authors: EC
authors: Lewis
authors: Department of Nephrology, Soroka Medical Center Beer-Sheva, Israel. Electronic address: cidio@bgu.ac.il.
authors: Cidio
authors: C
authors: Chaimovitz
authors: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Department of Nephrology, Soroka Medical Center Beer-Sheva, Israel. Electronic address: amosd@bgu.ac.il.
authors: Amos
authors: A
authors: Douvdevani
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000633:toxicity; D005354:Fibrosarcoma / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D003517:Cyclopentanes; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C071301:3-mercapto-3,3-cyclopentamethylenepropionic acid; D002110:Caffeine
keywords: 3-MCA; A(2A)R; Adenosine; Anti-tumor immunity; Caffeine