{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:52:36Z","timestamp":1790146356452,"version":"4.0.1"},"reference-count":100,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,9,7]],"date-time":"2019-09-07T00:00:00Z","timestamp":1567814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Currently, treatment is ineffective and the median overall survival is 20.9 months. The poor prognosis of GBM is a consequence of several altered signaling pathways that favor the proliferation and survival of neoplastic cells. One of these pathways is the deregulation of phosphodiesterases (PDEs). These enzymes participate in the development of GBM and may have value as therapeutic targets to treat GBM. Methylxanthines (MXTs) such as caffeine, theophylline, and theobromine are PDE inhibitors and constitute a promising therapeutic anti-cancer agent against GBM. MTXs also regulate various cell processes such as proliferation, migration, cell death, and differentiation; these processes are related to cancer progression, making MXTs potential therapeutic agents in GBM.<\/jats:p>","DOI":"10.3390\/ph12030130","type":"journal-article","created":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T04:12:40Z","timestamp":1568002360000},"page":"130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Methylxanthines: Potential Therapeutic Agents for Glioblastoma"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9712-2543","authenticated-orcid":false,"given":"Daniel","family":"P\u00e9rez-P\u00e9rez","sequence":"first","affiliation":[{"name":"PECEM, Faculty of Medicine, National Autonomous University of M\u00e9xico, M\u00e9xico City 04510, Mexico"},{"name":"Neuroimmunology and Neuro-oncology Unit, National Institute of Neurology and Neurosurgery, M\u00e9xico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9106-4103","authenticated-orcid":false,"given":"Iannel","family":"Reyes-Vidal","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuro-oncology Unit, National Institute of Neurology and Neurosurgery, M\u00e9xico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9566-2976","authenticated-orcid":false,"given":"Elda","family":"Ch\u00e1vez-Cortez","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuro-oncology Unit, National Institute of Neurology and Neurosurgery, M\u00e9xico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1313-8872","authenticated-orcid":false,"given":"Julio","family":"Sotelo","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuro-oncology Unit, National Institute of Neurology and Neurosurgery, M\u00e9xico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4667-1208","authenticated-orcid":false,"given":"Roxana","family":"Maga\u00f1a-Maldonado","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neuro-oncology Unit, National Institute of Neurology and Neurosurgery, M\u00e9xico City 14269, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"v1","DOI":"10.1093\/neuonc\/nox158","article-title":"CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010\u20132014","volume":"19","author":"Ostrom","year":"2017","journal-title":"Neuro Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12032-018-1083-x","article-title":"Cell biology of glioblastoma multiforme: From basic science to diagnosis and treatment","volume":"35","author":"Stoyanov","year":"2018","journal-title":"Med. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1001\/jama.2017.18718","article-title":"Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs. Maintenance Temozolomide Alone on Survival in Patients with Glioblastoma: A Randomized Clinical Trial","volume":"318","author":"Stupp","year":"2017","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"387","DOI":"10.2176\/nmc.ra.2016-0077","article-title":"Phenotypic Transition as a Survival Strategy of Glioma","volume":"56","author":"Ichikawa","year":"2016","journal-title":"Neurol. Med. Chir."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13223","DOI":"10.18632\/oncotarget.14656","article-title":"Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome","volume":"8","author":"Cesarini","year":"2017","journal-title":"Oncotarget"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"22194","DOI":"10.18632\/oncotarget.25175","article-title":"Natural products: A hope for glioblastoma patients","volume":"9","author":"Vengoji","year":"2018","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"333","DOI":"10.2174\/1381612825666190313123704","article-title":"Therapeutic Potential of Curcumin in the Treatment of Glioblastoma Multiforme","volume":"25","author":"Shahcheraghi","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1080\/01635581.2018.1446090","article-title":"Effects of the Green Tea Polyphenol Epigallocatechin-3-Gallate on Glioma: A Critical Evaluation of the Literature","volume":"70","author":"Le","year":"2018","journal-title":"Nutr. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Arnaud, M.J. (2011). Pharmacokinetics and metabolism of natural methylxanthines in animal and man. Handbook of Experimental Pharmacology, Springer.","DOI":"10.1007\/978-3-642-13443-2_3"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1210\/er.2013-1053","article-title":"Clinical and molecular genetics of the phosphodiesterases (PDEs)","volume":"35","author":"Azevedo","year":"2014","journal-title":"Endocr. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"325","DOI":"10.18869\/nirp.bcn.8.4.325","article-title":"The Role of Protein Kinase B Signaling Pathway in Anti-Cancer Effect of Rolipram on Glioblastoma Multiforme: An In Vitro Study","volume":"8","author":"Ramezani","year":"2017","journal-title":"Basic Clin. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.lfs.2011.12.010","article-title":"Phosphodiesterase inhibitors control A172 human glioblastoma cell death through cAMP-mediated activation of protein kinase A and Epac1\/Rap1 pathways","volume":"90","author":"Moon","year":"2012","journal-title":"Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"231","DOI":"10.2176\/nmc.11.231","article-title":"B-6. Effect of Cyclic AMP on the Malignant Brain Tumor Cells","volume":"11","author":"Nagai","year":"1971","journal-title":"Neurol. Med. Chir."},{"key":"ref_16","first-page":"2494","article-title":"Morphological Differentiation of Cultured Mouse Glioblastoma Cells Induced by Dibutyryl Cyclic Adenosine Monophosphate","volume":"35","author":"Sato","year":"1975","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15441","DOI":"10.1074\/jbc.M311844200","article-title":"cAMP-induced astrocytic differentiation of C6 glioma cells is mediated by autocrine interleukin-6","volume":"279","author":"Takanaga","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1080\/01635581.2013.877497","article-title":"Theobromine, the primary methylxanthine found in Theobroma cacao, prevents malignant glioblastoma proliferation by negatively regulating phosphodiesterase-4, extracellular signal-regulated kinase, Akt\/mammalian target of rapamycin kinase, and nuclear fact","volume":"66","author":"Sugimoto","year":"2014","journal-title":"Nutr. Cancer"},{"key":"ref_19","first-page":"110","article-title":"Cytosine arabinoside plus cisplatin and other drugs as chemotherapy for gliomas","volume":"14","author":"Stewart","year":"1987","journal-title":"Semin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1006\/excr.1998.4122","article-title":"Caffeine and staurosporine enhance the cytotoxicity of cisplatin and camptothecin in human brain tumor cell lines","volume":"243","author":"Janss","year":"1998","journal-title":"Exp. Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1159\/000362966","article-title":"Caffeine inhibits migration in glioma cells through the ROCK-FAK pathway","volume":"33","author":"Chen","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1158\/1535-7163.MCT-09-0498","article-title":"Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation-Induced G1 Arrest and Negatively Regulating Akt Phosphorylation","volume":"9","author":"Sinn","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s10059-011-0027-5","article-title":"Caffeine inhibits cell proliferation and regulates PKA\/GSK3\u03b2 pathways in U87MG human glioma cells","volume":"31","author":"Ku","year":"2011","journal-title":"Mol. Cells"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kleppisch, T. (2009). Phosphodiesterases in the central nervous system. Handbook of Experimental Pharmacology, Springer.","DOI":"10.1007\/978-3-540-68964-5_5"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.semcancer.2018.08.011","article-title":"Targeting the paracrine hormone-dependent guanylate cyclase\/cGMP\/phosphodiesterases signaling pathway for colorectal cancer prevention","volume":"56","author":"Yarla","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19532","DOI":"10.1073\/pnas.0806152105","article-title":"Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia","volume":"105","author":"Zhang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1471-4159.2005.03028.x","article-title":"Differential phosphodiesterase expression and cytosolic Ca2+ in human CNS tumour cells and in non-malignant and malignant cells of rat origin","volume":"93","author":"Vatter","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7717","DOI":"10.1158\/1078-0432.CCR-08-0827","article-title":"Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression","volume":"14","author":"Goldhoff","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/mc.22276","article-title":"Cyclic nucleotide phosphodiesterase-1C (PDE1C) drives cell proliferation, migration and invasion in glioblastoma multiforme cells in vitro","volume":"55","author":"Rowther","year":"2016","journal-title":"Mol. Carcinog."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/S0167-4781(00)00293-1","article-title":"Human Ca2+\/calmodulin-dependent phosphodiesterase PDE1A: Novel splice variants, their specific expression, genomic organization, and chromosomal localization","volume":"1517","author":"Michibata","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s003359900820","article-title":"Genomic structure and chromosome location of the murine PDE1B phosphodiesterase gene","volume":"9","author":"Reed","year":"1998","journal-title":"Mamm. Genome"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1074\/jbc.271.2.796","article-title":"Isolation and characterization of cDNAs corresponding to two human calcium, calmodulin-regulated, 3\u2032,5\u2032-cyclic nucleotide phosphodiesterases","volume":"271","author":"Loughney","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0378-1119(97)00046-2","article-title":"Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3\u2032,5\u2032-cyclic nucleotide phosphodiesterase","volume":"191","author":"Rosman","year":"1997","journal-title":"Gene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.cancergen.2016.09.001","article-title":"Co-localized genomic regulation of miRNA and mRNA via DNA methylation affects survival in multiple tumor types","volume":"209","author":"Doecke","year":"2016","journal-title":"Cancer Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3721","DOI":"10.1073\/pnas.89.9.3721","article-title":"Molecular cloning and expression of human myocardial cGMP-inhibited cAMP phosphodiesterase","volume":"89","author":"Meacci","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.cellsig.2019.05.011","article-title":"Cyclic nucleotide phosphodiesterases (PDEs) and endothelial function in ischaemic stroke. A review","volume":"61","author":"Yasmeen","year":"2019","journal-title":"Cell. Signal."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1006\/geno.1996.0493","article-title":"Characterization of the cDNA and gene encoding human PDE3B, the cGIP1 isoform of the human cyclic GMP-inhibited cyclic nucleotide phosphodiesterase family","volume":"36","author":"Miki","year":"1996","journal-title":"Genomics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1161\/01.RES.0000261934.56938.38","article-title":"cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: A molecular toolbox for generating compartmentalized cAMP signaling","volume":"100","author":"Houslay","year":"2007","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5493","DOI":"10.1074\/jbc.R200029200","article-title":"Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling","volume":"278","author":"Conti","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.lfs.2017.02.005","article-title":"Rolipram potentiates bevacizumab-induced cell death in human glioblastoma stem-like cells","volume":"173","author":"Ramezani","year":"2017","journal-title":"Life Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"250","DOI":"10.3892\/or.2014.3176","article-title":"Integrated analysis using methylation and gene expression microarrays reveals PDE4C as a prognostic biomarker in human glioma","volume":"32","author":"Bao","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/sj.ijir.3900802","article-title":"Human PDE5A gene encodes three PDE5 isoforms from two alternate promoters","volume":"14","author":"Lin","year":"2002","journal-title":"Int. J. Impot. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/j.1399-0004.2010.01487.x","article-title":"Identification of a novel mutation in the human PDE6A gene in autosomal recessive retinitis pigmentosa: Homology with the nmf28\/nmf28 mice model","volume":"78","author":"Corton","year":"2010","journal-title":"Clin. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1080\/13816810.2018.1509354","article-title":"Structural disease progression in PDE6-associated autosomal recessive retinitis pigmentosa","volume":"39","author":"Takahashi","year":"2018","journal-title":"Ophthalmic Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1006\/geno.1995.1171","article-title":"Gene structure and amino acid sequence of the human cone photoreceptor cGMP-phosphodiesterase alpha\u2019 subunit (PDEA2) and its chromosomal localization to 10q24","volume":"28","author":"Piriev","year":"1995","journal-title":"Genomics"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Brooks, M.D., Jackson, E., Warrington, N.M., Luo, J., Forys, J.T., Taylor, S., Mao, D.D., Leonard, J.R., Kim, A.H., and Piwnica-Worms, D. (2014). PDE7B is a novel, prognostically significant mediator of glioblastoma growth whose expression is regulated by endothelial cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107397"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1006\/geno.1997.5168","article-title":"Assignment of the mouse Pde7A gene to the proximal region of chromosome 3 and of the human PDE7A gene to chromosome 8q13","volume":"48","author":"Han","year":"1998","journal-title":"Genomics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1073\/pnas.97.1.472","article-title":"Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase","volume":"97","author":"Hetman","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.cellimm.2009.04.005","article-title":"Phosphodiesterase 7A inhibitor ASB16165 suppresses proliferation and cytokine production of NKT cells","volume":"258","author":"Goto","year":"2009","journal-title":"Cell. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0378-1119(01)00783-1","article-title":"Human phosphodiesterase 8A splice variants: Cloning, gene organization, and tissue distribution","volume":"280","author":"Wang","year":"2001","journal-title":"Gene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/S0006-291X(02)02371-9","article-title":"Genomic organization, chromosomal localization, and alternative splicing of the human phosphodiesterase 8B gene","volume":"297","author":"Hayashi","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.cellsig.2017.08.007","article-title":"PDE8 controls CD4+ T cell motility through the PDE8A-Raf-1 kinase signaling complex","volume":"40","author":"Basole","year":"2017","journal-title":"Cell. Signal."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4489","DOI":"10.1172\/JCI75284","article-title":"miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways","volume":"124","author":"Wang","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1007\/s004390050838","article-title":"Identification and characterization of a novel cyclic nucleotide phosphodiesterase gene (PDE9A) that maps to 21q22.3: Alternative splicing of mRNA transcripts, genomic structure and sequence","volume":"103","author":"Guipponi","year":"1998","journal-title":"Hum. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/978-3-319-58811-7_9","article-title":"Role of PDE9 in Cognition","volume":"17","author":"Kroker","year":"2017","journal-title":"Adv. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"18438","DOI":"10.1074\/jbc.274.26.18438","article-title":"Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)","volume":"274","author":"Fujishige","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1016\/j.neuron.2016.10.064","article-title":"Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington\u2019s Disease Models","volume":"92","author":"Beaumont","year":"2016","journal-title":"Neuron"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1158\/1541-7786.MCR-08-0270","article-title":"High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray","volume":"7","author":"Yin","year":"2009","journal-title":"Mol. Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.ejmech.2018.03.046","article-title":"Inhibitors of phosphodiesterase as cancer therapeutics","volume":"150","author":"Peng","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Monteiro, J.P., Alves, M.G., Oliveira, P.F., and Silva, B.M. (2016). Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks. Molecules, 21.","DOI":"10.3390\/molecules21080974"},{"key":"ref_61","first-page":"1","article-title":"Xanthine Alkaloids: Occurrence, Biosynthesis, and Function in Plants","volume":"105","author":"Ashihara","year":"2017","journal-title":"Prog. Chem. Org. Nat. Prod."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Basnet, R.M., Zizioli, D., Guarienti, M., Finazzi, D., and Memo, M. (2017). Methylxanthines induce structural and functional alterations of the cardiac system in zebrafish embryos. BMC Pharmacol. Toxicol., 18.","DOI":"10.1186\/s40360-017-0179-9"},{"key":"ref_63","first-page":"112","article-title":"Theophylline, a new look to an old drug","volume":"57","year":"2010","journal-title":"Rev. Alerg. Mex."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nrd3955","article-title":"Adenosine receptors as drug targets\u2014What are the challenges?","volume":"12","author":"Chen","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Fishman, P., Bar-Yehuda, S., Synowitz, M., Powell, J.D., Klotz, K.N., Gessi, S., and Borea, P.A. (2009). Adenosine receptors and cancer. Handbook of Experimental Pharmacology, Springer.","DOI":"10.1007\/978-3-540-89615-9_14"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"67373","DOI":"10.18632\/oncotarget.12033","article-title":"Adenosine A3 receptor elicits chemoresistance mediated by multiple resistance-associated protein-1 in human glioblastoma stem-like cells","volume":"7","author":"Torres","year":"2016","journal-title":"Oncotarget"},{"key":"ref_67","first-page":"625","article-title":"Known and hidden sources of caffeine in drug, food, and natural products","volume":"42","author":"Durrant","year":"2002","journal-title":"J. Am. Pharm. Assoc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1093\/jat\/bkx011","article-title":"Review of Caffeine-Related Fatalities along with Postmortem Blood Concentrations in 51 Poisoning Deaths","volume":"41","author":"Jones","year":"2017","journal-title":"J. Anal. Toxicol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"j5024","DOI":"10.1136\/bmj.j5024","article-title":"Coffee consumption and health: Umbrella review of meta-analyses of multiple health outcomes","volume":"359","author":"Poole","year":"2017","journal-title":"BMJ"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1146\/annurev-nutr-071816-064941","article-title":"Coffee, Caffeine, and Health Outcomes: An Umbrella Review","volume":"37","author":"Durrant","year":"2017","journal-title":"Annu. Rev. Nutr."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2174\/1570159X13666141210215655","article-title":"Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?","volume":"13","author":"Cappelletti","year":"2015","journal-title":"Curr. Neuropharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s10194-017-0806-2","article-title":"Caffeine in the management of patients with headache","volume":"18","author":"Lipton","year":"2017","journal-title":"J. Headache Pain"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1080\/10903127.2017.1382624","article-title":"Systematic Review and Meta-analysis of the Effects of Caffeine in Fatigued Shift Workers: Implications for Emergency Medical Services Personnel","volume":"22","author":"Temple","year":"2018","journal-title":"Prehosp. Emerg. Care"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e33193","DOI":"10.5812\/aapm.33193","article-title":"The Role of Caffeine in Pain Management: A Brief Literature Review","volume":"6","author":"Baratloo","year":"2016","journal-title":"Anesthesiol. Pain Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"270","DOI":"10.3389\/fphys.2014.00270","article-title":"Combination ergotamine and caffeine improves seated blood pressure and presyncopal symptoms in autonomic failure","volume":"5","author":"Arnold","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s00210-015-1189-z","article-title":"Caffeine enhances the antidepressant-like activity of common antidepressant drugs in the forced swim test in mice","volume":"389","author":"Szopa","year":"2016","journal-title":"Naunyn-Schmiedebergs Arch. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.cjtee.2015.10.003","article-title":"Chronic caffeine exposure attenuates blast-induced memory deficit in mice","volume":"18","author":"Ning","year":"2015","journal-title":"Chin. J. Traumatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/sj.jcbfm.9600539","article-title":"Increases in Cerebrospinal Fluid Caffeine Concentration are Associated with Favorable Outcome after Severe Traumatic Brain injury in Humans","volume":"28","author":"Sachse","year":"2008","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3233\/JAD-142223","article-title":"Caffeine, Through Adenosine A3Receptor-Mediated Actions, Suppresses Amyloid-\u03b2 Protein Precursor Internalization and Amyloid-\u03b2 Generation","volume":"47","author":"Li","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/19390211.2016.1275916","article-title":"Neuroprotective and Therapeutic Effect of Caffeine on the Rat Model of Parkinson\u2019s Disease Induced by Rotenone","volume":"14","author":"Khadrawy","year":"2017","journal-title":"J. Diet. Suppl."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12957-019-1591-y","article-title":"Association between tea and coffee consumption and brain cancer risk: An updated meta-analysis","volume":"17","author":"Song","year":"2019","journal-title":"World J. Surg. Oncol."},{"key":"ref_82","first-page":"3201","article-title":"The in vitro effects of caffeine on viability, cycle cycle profiles, proliferation, and apoptosis of glioblastomas","volume":"19","author":"Jiang","year":"2015","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1007\/s13277-015-4180-x","article-title":"Caffeine-induced nuclear translocation of FoxO1 triggers Bim-mediated apoptosis in human glioblastoma cells","volume":"37","author":"Sun","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1080\/01635581.2014.902974","article-title":"Tetrandrine and Caffeine Modulated Cell Cycle and Increased Glioma Cell Death via Caspase-Dependent and Caspase-Independent Apoptosis Pathways","volume":"66","author":"Chen","year":"2014","journal-title":"Nutr. Cancer"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.tcmj.2016.06.005","article-title":"Effects of caffeine on cell viability and activity of histone deacetylase 1 and histone acetyltransferase in glioma cells","volume":"28","author":"Chen","year":"2016","journal-title":"Tzu Chi Med. J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1158\/0008-5472.CAN-09-2886","article-title":"Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival","volume":"70","author":"Kang","year":"2010","journal-title":"Cancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jnutbio.2016.03.004","article-title":"Caffeine suppresses the progression of human glioblastoma via cathepsin B and MAPK signaling pathway","volume":"33","author":"Cheng","year":"2016","journal-title":"J. Nutr. Biochem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.2174\/1871520618666180209151750","article-title":"Caffeine Effect on HIFs\/VEGF Pathway in Human Glioblastoma Cells Exposed to Hypoxia","volume":"18","author":"Maugeri","year":"2018","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"26","DOI":"10.2174\/1566524014666141203143143","article-title":"Tea (Camellia sinensis (L.)): A putative anticancer agent in bladder carcinoma?","volume":"15","author":"Conde","year":"2015","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1600670","DOI":"10.1002\/mnfr.201600670","article-title":"Health benefits of methylxanthines in neurodegenerative diseases","volume":"61","author":"Franco","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1513\/pats.200504-024SR","article-title":"Theophylline in chronic obstructive pulmonary disease: New horizons","volume":"2","author":"Barnes","year":"2005","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"725","DOI":"10.3390\/ph3030725","article-title":"Theophylline","volume":"3","author":"Barnes","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"21741","DOI":"10.18632\/oncotarget.15566","article-title":"Preclinical therapeutic efficacy of a novel blood-brain barrier-penetrant dual PI3K\/mTOR inhibitor with preferential response in PI3K\/PTEN mutant glioma","volume":"8","author":"Koul","year":"2017","journal-title":"Oncotarget"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"265","DOI":"10.2147\/DDDT.S118485","article-title":"Theophylline action on primary human bronchial epithelial cells under proinflammatory stimuli and steroidal drugs: A therapeutic rationale approach","volume":"11","author":"Gallelli","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3648","DOI":"10.7150\/jca.21783","article-title":"Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer","volume":"8","author":"Domvri","year":"2017","journal-title":"J. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"101461","DOI":"10.18632\/oncotarget.21464","article-title":"Theophylline exhibits anti-cancer activity via suppressing SRSF3 in cervical and breast cancer cell lines","volume":"8","author":"Chang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.phrs.2009.08.008","article-title":"Theobroma cacao L., the Food of the Gods: A scientific approach beyond myths and claims","volume":"61","author":"Rusconi","year":"2010","journal-title":"Pharmacol. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1093\/jnci\/50.2.555","article-title":"Cyclic adenosine 3\u2032,5\u2032-monophosphate in the control of melanoma cell replication and differentiation","volume":"50","author":"Kreider","year":"1973","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_99","first-page":"482","article-title":"Association of tumor differentiation with caffeine and coffee intake in women with breast cancer","volume":"100","author":"Pozner","year":"1986","journal-title":"Surgery"},{"key":"ref_100","first-page":"43","article-title":"Enhancement of cytocidal and antitumor effect of cisplatin by caffeine in human osteosarcoma","volume":"11","author":"Tomita","year":"1989","journal-title":"Clin. Ther."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/12\/3\/130\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:17:32Z","timestamp":1760188652000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/12\/3\/130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,7]]},"references-count":100,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["ph12030130"],"URL":"https:\/\/doi.org\/10.3390\/ph12030130","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,7]]}}}