Methylxanthines: Potential Therapeutic Agents for Glioblastoma
Abstract
:1. Introduction
2. Phosphodiesterases in Glioblastoma (GBM)
3. Methylxanthines
3.1. Caffeine
3.2. Theophylline
3.3. Theobromine
4. Methylxanthines and Cellular Differentiation
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Main Author (Reference) | Methylxanthine | Type of Study | Relevant Methodology | Relevant Results |
---|---|---|---|---|
Moon et al., 2012 [14] | Theophylline | In vitro | A-172 and U87MG cell lines | Reduces the survival and proliferation |
Nagai et al., 1971 [15] | Theophylline | In vitro | Human glioblastoma cells and glioma cells induced by MC in C57 black mouse | Induces morphological changes |
Sato et al., 1975 [16] | Theophylline | In vitro | Mouse glioma cell line | Induces glial-like morphological changes and expression of S-100 protein. |
Takanaga et al., 2004 [17] | Theophylline | In vitro | C6 cell line | N6,2′-O-dibutyryl cAMP (Bt2AMP) and theophylline caused delayed phosphorylation of STAT3 and expression of GFAP. |
Sugimoto et al., 2014 [18] | Theobromine | In vitro | U87MG cell line | Anti-tumoral and anti-inflammatory effects. Inhibits proliferation and induces apoptosis. |
Stewart et al., 1987 [19] | Caffeine | Clinical | 25 patients with gliomas Caffeine added to cytosine arabinoside plus cisplatin | Presence of caffeine-induced seizures 48% of the patients responded. |
Janss et al., 1998 [20] | Caffeine | In vitro | U251 glioma cells | Caffeine reduced the ID50 and ID90 of cisplatin promoting apoptosis. |
Chen et al., 2014 [21] | Caffeine | In vitro | C6 and U87MG cell lines | Caffeine decreases migration by inhibition of ROCK-focal adhesion complex pathway. |
Sinn et al., 2010 [22] | Caffeine | In vitro | U87MG, T98G and U373MG cells lines | Inhibits PI3K, downregulating the PI3K/Akt pathway and induces apoptosis. |
Ku et al., 2011 [23] | Caffeine | In vivo | Mouse xenograft model of GBM | Inhibits of the IP3R3. |
Phosphodiesterase | Gene Chromosome | Substrate | Main Function | Participation in GBM | Ref. |
---|---|---|---|---|---|
PDE1 | PDE1A, B, C 2q32.1, 12q13.2, 7q14.3 | cAMP and cGMP | Promotes cell proliferation and migration | PDE1C is overexpressed on GBM | [29,30,31,32] |
PDE2 | PDE2A 11q13.4 | cAMP and cGMP | Regulates endothelial permeability and proliferation and nNOS expression. | PDE2A is overexpressed in low grade glioma | [33,34] |
PDE3 | PDE3A, B 12q12.2, 11p15.2 | cAMP and cGMP | Smooth muscle contraction, insulin signaling, blood vessel formation, and antiapoptotic and anti-inflammatory pathways | N. D. | [35,36,37] |
PDE4 | PDE4A, B, C, D 19p13.2, 1p31.3, 19p13.11, 5p11.2-q12.1 | cAMP | Promotes blood vessel formation, monocyte and macrophage activation, and antiapoptotic and anti-inflammatory pathways | PDE4 promotes the tumor growth Hypermethylation of the PDE4C promoter is associated with high malignant grade and reduced overall survival | [36,38,39,40,41] |
PDE5 | PDE5A 4q26 | cGMP | Regulates cell signaling | PDE5 is overexpression correlates with longer overall survival, and its inhibition induces an invasive phenotype of GBM | [7,42] |
PDE6 | PDE6A, B, C 5q32, 4p16.3, 10q24 | cGMP | Participates in rod and cone photoreceptor function | N. D. | [43,44,45] |
PDE7 | PDE7A, B 8q13, 6q23-24 | cAMP | Modulation of T-cell proliferation | PDE7B overexpression induces tumor growth | [46,47,48,49] |
PDE8 | PDE8A, B 15q25.3, 15q13.3 | cAMP | Controls T cells and breast cancer cells motility | PDE8A expression correlates with an increased overall survival | [50,51,52,53] |
PDE9 | PDE9A 21q22.3 | cGMP | Participates in synaptic plasticity and cognitive function | N. D. | [54,55] |
PDE10 | PDE10A 6q26 | cAMP and cGMP | Regulates intracellular signaling and controls striatal gene expression | PDE10A is deleted on GBM tissue | [56,57,58] |
PDE11 | PDE11A 2q31.2 | cAMP and cGMP | Contributes to sperm development | N. D. | [59] |
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Pérez-Pérez, D.; Reyes-Vidal, I.; Chávez-Cortez, E.G.; Sotelo, J.; Magaña-Maldonado, R. Methylxanthines: Potential Therapeutic Agents for Glioblastoma. Pharmaceuticals 2019, 12, 130. https://doi.org/10.3390/ph12030130
Pérez-Pérez D, Reyes-Vidal I, Chávez-Cortez EG, Sotelo J, Magaña-Maldonado R. Methylxanthines: Potential Therapeutic Agents for Glioblastoma. Pharmaceuticals. 2019; 12(3):130. https://doi.org/10.3390/ph12030130
Chicago/Turabian StylePérez-Pérez, Daniel, Iannel Reyes-Vidal, Elda Georgina Chávez-Cortez, Julio Sotelo, and Roxana Magaña-Maldonado. 2019. "Methylxanthines: Potential Therapeutic Agents for Glioblastoma" Pharmaceuticals 12, no. 3: 130. https://doi.org/10.3390/ph12030130