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 Factor-Kappa B

REFERENCES

• Hurst , W J , Tarka , S M Jr , Powis , T G , Valdez , F Jr and Hester , T R . 2002 . Cacao usage by the earliest Maya civilization . Nature , 418 : 289 – 290 .
   PubMed Web of Science ®Google Scholar
• Ramiro-Puig , E and Castell , M . 2009 . Cocoa: antioxidant and immunomodulator . Br J Nutr , 101 : 931 – 940 .
   PubMed Web of Science ®Google Scholar
• Visioli , F , Bernaert , H , Corti , R , Ferri , C Heptinstall , S . 2009 . Chocolate, lifestyle, and health . Crit Rev Food Sci Nutr , 49 : 299 – 312 .
   PubMed Web of Science ®Google Scholar
• Lee , K W , Kim , Y J , Lee , H J and Lee , C Y . 2003 . Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine . J Agric Food Chem , 51 : 7292 – 7295 .
   PubMed Web of Science ®Google Scholar
• Rusconi , M and Conti , A . 2010 . Theobroma cacao L., the food of the gods: a scientific approach beyond myths and claims . Pharmacol Res , 61 : 5 – 13 .
   PubMed Web of Science ®Google Scholar
• Vinson , J A , Proch , J and Zubik , L . 1999 . Phenol antioxidant quantity and quality in foods: cocoa, dark chocolate, and milk chocolate . J Agric Food Chem , 47 : 4821 – 4824 .
   PubMed Web of Science ®Google Scholar
• Pura Naik , J . 2001 . Improved high-performance liquid chromatography method to determine theobromine and caffeine in cocoa and cocoa products . J Agric Food Chem , 49 : 3579 – 3583 .
   PubMed Web of Science ®Google Scholar
• Wells , J N , Wu , Y J , Baird , C E and Hardman , J G . 1975 . Phosphodiesterases from porcine coronary arteries: inhibition of separated forms by xanthines, papaverine, and cyclic nucleotides . Mol Pharmacol , 11 : 775 – 783 .
   PubMed Web of Science ®Google Scholar
• Miwa , S , Sugimoto , N , Shirai , T , Hayashi , K Nishida , H . 2011 . Caffeine activates tumor suppressor PTEN in sarcoma cells . Int J Oncol , 39 : 465 – 472 .
   PubMed Web of Science ®Google Scholar
• Miwa , S , Sugimoto , N , Yamamoto , N , Shirai , T Nishida , H . 2012 . Caffeine induces apoptosis of osteosarcoma cells by inhibiting AKT/mTOR/S6K, NF-κB and MAPK pathways . Anticancer Res , 32 : 3643 – 3649 .
   PubMed Web of Science ®Google Scholar
• Saito , T , Sugimoto , N , Ohta , K , Shimizu , T Ohtani , K . 2012 . Phosphodiesterase inhibitors suppress Lactobacillus casei cell-wall-induced NF-κB and MAPK activations and cell proliferation through protein kinase A—or exchange protein activated by cAMP-dependent signal pathway . Scientific World Journal , 2012 : 748572 – 8 . 1
   Web of Science ®Google Scholar
• McCubrey , J A , Steelman , L S , Abrams , S L , Lee , J T Chang , F . 2006 . Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance . Adv Enzyme Regul , 46 : 249 – 279 .
   PubMedGoogle Scholar
• Hers , I , Vincent , E E and Tavaré , J M . 2011 . Akt signalling in health and disease . Cell Signal , 23 : 1515 – 1527 .
   PubMed Web of Science ®Google Scholar
• Goldhoff , P , Warrington , N M , Limbrick , D D Jr , Hope , A Woerner , B M . 2008 . Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression . Clin Cancer Res , 14 : 7717 – 7725 .
   PubMed Web of Science ®Google Scholar
• Brown , J A , Gianino , S M and Gutmann , D H . 2010 . Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity . J Neurosci , 30 : 5579 – 5589 .
   PubMed Web of Science ®Google Scholar
• Warrington , N M , Gianino , S M , Jackson , E , Goldhoff , P Garbow , J R . 2010 . Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1 . Cancer Res , 70 : 5717 – 5727 .
   PubMed Web of Science ®Google Scholar
• Yang , L , Jackson , E , Woerner , B M , Perry , A Piwnica-Worms , D . 2007 . Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo . Cancer Res , 67 : 651 – 658 .
   PubMed Web of Science ®Google Scholar
• Sengupta , R , Sun , T , Warrington , N M and Rubin , J B . 2011 . Treating brain tumors with PDE4 inhibitors . Trends Pharmacol Sci , 32 : 337 – 344 .
   PubMed Web of Science ®Google Scholar
• Karin , M and Lin , A . 2002 . NF-κB at the crossroads of life and death . Nat Immunol , 3 : 221 – 227 .
   PubMed Web of Science ®Google Scholar
• Tomonaga , M , Hashimoto , N , Tokunaga , F , Onishi , M Myoui , A . 2012 . Activation of nuclear factor-kappa B by linear ubiquitin chain assembly complex contributes to lung metastasis of osteosarcoma cells . Int J Oncol , 40 : 409 – 417 .
   PubMed Web of Science ®Google Scholar
• Sugimoto , N , Miwa , S , Ohno-Shosaku , T , Tsuchiya , H Hitomi , Y . 2011 . Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells . Neurosci Lett , 497 : 55 – 59 .
   PubMed Web of Science ®Google Scholar
• Comerford , K M , Lawrence , D W , Synnestvedt , K , Levi , B P and Colgan , S P . 2002 . Role of vasodilator-stimulated phosphoprotein in PKA-induced changes in endothelial junctional permeability . FASEB J , 16 : 583 – 585 .
   PubMed Web of Science ®Google Scholar
• Loza , M J , Foster , S , Peters , S P and Penn , R B . 2006 . Beta-agonists modulate T-cell functions via direct actions on type 1 and type 2 cells . Blood , 107 : 2052 – 2060 .
   PubMed Web of Science ®Google Scholar
• Sugimoto , N , Miwa , S , Tsuchiya , H , Hitomi , Y Nakamura , H . 2013 . Targeted activation of PKA and Epac promotes glioblastoma regression in vitro . Mol Clin Oncol , 1 : 281 – 285 .
   PubMedGoogle Scholar
• Gong , X , Luo , T , Deng , P , Liu , Z Xiu , J . 2012 . Stress-induced interaction between p38 MAPK and HSP70 . Biochem Biophys Res Commun , 425 : 357 – 362 .
   PubMed Web of Science ®Google Scholar
• Parsa , A T and Holland , E C . 2004 . Cooperative translational control of gene expression by Ras and Akt in cancer . Trends Mol Med , 10 : 607 – 613 .
   PubMed Web of Science ®Google Scholar
• Xia , Z , Dickens , M , Raingeaud , J , Davis , R J and Greenberg , M E . 1995 . Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis . Science , 270 : 1326 – 1331 .
   PubMed Web of Science ®Google Scholar
• Zhou , H and Huang , S . 2011 . Role of mTOR signaling in tumor cell motility, invasion and metastasis . Curr Protein Pept Sci , 12 : 30 – 42 .
   PubMed Web of Science ®Google Scholar
• Qu , Y , Zhang , J , Wu , S , Li , B Liu , S . 2012 . SIRT1 promotes proliferation and inhibits apoptosis of human malignant glioma cell lines . Neurosci Lett , 525 : 168 – 172 .
   PubMed Web of Science ®Google Scholar
• Echigo , R , Sugimoto , N , Yachie , A and Ohno-Shosaku , T . 2012 . Cannabinoids inhibit peptidoglycan-induced phosphorylation of NF-κB and cell growth in U87MG human malignant glioma cells . Oncol Rep , 28 : 1176 – 1180 .
   PubMed Web of Science ®Google Scholar
• Basseres , D S and Baldwin , A S . 2006 . Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression . Oncogene , 25 : 6817 – 6830 .
   PubMed Web of Science ®Google Scholar
• Karin , M . 2006 . Nuclear factor-kappaB in cancer development and progression . Nature , 441 : 431 – 436 .
   PubMed Web of Science ®Google Scholar
• Aggarwal , B B . 2004 . Nuclear factor-kappaB: the enemy within . Cancer Cell , 6 : 203 – 208 .
   PubMed Web of Science ®Google Scholar
• Prasad , S , Ravindran , J and Aggarwal , B B . 2010 . NF-kappaB and cancer: how intimate is this relationship . Mol Cell Biochem , 336 : 25 – 37 .
   PubMed Web of Science ®Google Scholar
• Holland , E C , Celestino , J , Dai , C , Schaefer , L Sawaya , R E . 2000 . Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice . Nat Genet , 25 : 55 – 57 .
   PubMed Web of Science ®Google Scholar
• Höland , K , Salm , F and Arcaro , A . 2011 . The phosphoinositide 3-kinase signaling pathway as a therapeutic target in grade IV brain tumors . Curr Cancer Drug Targets , 11 : 894 – 918 .
   PubMed Web of Science ®Google Scholar