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A. Monoclonal antibodies against PD-1 can induce the increase synthesis of IFN-γ by T lymphocytes, with increase of interferon regulatory fator-8 (IRF8) that binds to the MDM2 promoter inducing MDM2 amplification in tumor cells. This results in suppression of p53, with tumor growth and progression. B. The use of phosphodiesterase inhibitors promotes increase levels of cAMP, diminishing the production of IFN-γ, expression of IRF8 and MDM2 amplification. In turn, not occurring suppression of p53, or tumor growth and progression. APC=Antigen presenting cell; MHC=Major histocompatibility complex; mAB=Monoclonal antibody. B. Increase in the expression of MDM2.
Source publication
Cell signaling is a crucial event for the survival and
progress of normal cellular functions. However, mutations
of certain genes can lead to the emerging of cancer cells,
which can use these signaling mechanisms for their
survival, growth and dissemination. Among these
mechanisms, we highlight the role of cyclic nucleotides
such as cAMP, and Ca2+...
Contexts in source publication
Context 1
... antibodies against PD-1 can induce the increase synthesis of interferon gamma (IFN-γ) by T lymphocytes [67], which in turn activates JAK-STAT signaling [68] resulting in increase of interferon regulatory fator-8 (IRF8) expression [69]. Finally, the IRF8 binds to the MDM2 promoter inducing MDM2 higher expression [70] shown in Figure 1A. Because the elevation of intracellular cAMP creates an oxidative environment that oxidizes and inactivates p56(lck) in lymphocytes by an H 2 O 2 dependent, PKA-independent mechanism, and inhibits the production of IFN-γ by nitric oxide, PKA-dependent mechanism [71], the use of phosphodiesterase inhibitors can promote the increase levels of cAMP [72], hindering the production of IFN-γ, which would make difficult to increase the expression of IRF8, and increase in the expression of MDM2 shown in Figure 1B. ...
Context 2
... the IRF8 binds to the MDM2 promoter inducing MDM2 higher expression [70] shown in Figure 1A. Because the elevation of intracellular cAMP creates an oxidative environment that oxidizes and inactivates p56(lck) in lymphocytes by an H 2 O 2 dependent, PKA-independent mechanism, and inhibits the production of IFN-γ by nitric oxide, PKA-dependent mechanism [71], the use of phosphodiesterase inhibitors can promote the increase levels of cAMP [72], hindering the production of IFN-γ, which would make difficult to increase the expression of IRF8, and increase in the expression of MDM2 shown in Figure 1B. ...
Similar publications
Due to structural and functional abnormalities or genetic variations and mutations, there may be dysfunctional molecules within an intracellular signaling network that do not allow the network to correctly regulate its output molecules, such as transcription factors. This disruption in signaling interrupts normal cellular functions and may eventual...
Citations
... Cyclic adenosine monophosphate (cAMP) is a second messenger that has a major role in transduction and cell signaling in several pathways and biological systems [1]. cAMP elevation may be achieved via the activation of the adenylate cyclases by Gs proteins, and the inhibition of cAMP-degrading phosphodiesterases [2], and has been shown to inhibit proliferation of several cancer cell types such as breast cancer, colon cancer, lung cancer, glioblastoma etc [3][4][5][6]. ...
... Additionally compounds 1, 4 and 5 (with the highest predicted affinities and the most potent agonists identified), compound 6 (which did not exhibit any agonist activity), CHEMBL3799351 (an antagonist with an IC 50 = 4.35 nM and confidence score equal to 9) and CGS21680 (the selective and potent A 2A R agonist) and adenosine (a non-selective adenosine receptor agonist), were docked into the inactive form of the A 2A R protein crystal structure (PDB ID: 5IU4) for MD simulation and analysis. The six triazoloquinazolines (1)(2)(3)(4)(5)(6) were then shortlisted for validation as A 2A R agonists in relevant biochemical assays. ...
Enhanced/prolonged cAMP signalling has been suggested as a suppressor of cancer proliferation. Interestingly, two key modulators that elevate cAMP, the A2A receptor (A2AR) and phosphodiesterase 10A (PDE10A), are differentially co-expressed in various types of non-small lung cancer (NSCLC) cell-lines. Thus, finding dual-target compounds, which are simultaneously agonists at the A2AR whilst also inhibiting PDE10A, could be a novel anti-proliferative approach. Using ligand- and structure-based modelling combined with MD simulations (which identified Val84 displacement as a novel conformational descriptor of A2AR activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A2AR. Subsequent in-vitro analysis confirmed that these compounds bind to the A2AR and exhibit dual-activity at both the A2AR and PDE10A. Furthermore, many of the compounds exhibited promising anti-proliferative effects upon NSCLC cell-lines, which directly correlated with the expression of both PDE10A and the A2AR. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value.
... Cyclic adenosine monophosphate (cAMP) is a second messenger that has a major role in transduction and cell signaling in several pathways and biological systems [1]. cAMP elevation may be achieved via the activation of the adenylate cyclases by Gs proteins, and the inhibition of cAMP-degrading phosphodiesterases [2], and has been shown to inhibit proliferation of several cancer cell types such as breast cancer, colon cancer, lung cancer, glioblastoma etc [3][4][5][6]. ...
... Additionally compounds 1, 4 and 5 (with the highest predicted affinities and the most potent agonists identified), compound 6 (which did not exhibit any agonist activity), CHEMBL3799351 (an antagonist with an IC 50 = 4.35 nM and confidence score equal to 9) and CGS21680 (the selective and potent A 2A R agonist) and adenosine (a non-selective adenosine receptor agonist), were docked into the inactive form of the A 2A R protein crystal structure (PDB ID: 5IU4) for MD simulation and analysis. The six triazoloquinazolines (1)(2)(3)(4)(5)(6) were then shortlisted for validation as A 2A R agonists in relevant biochemical assays. ...
Enhanced/prolonged cAMP signalling has been suggested as a suppressor of cancer proliferation. Interestingly, two key modulators that elevate cAMP, the A 2A receptor (A 2A R) and phosphodiesterase 10A (PDE10A), are differentially co-expressed in various types of non-small lung cancer (NSCLC) cell-lines. Thus, finding dual-target compounds, which are simultaneously agonists at the A 2A R whilst also inhibiting PDE10A, could be a novel anti-proliferative approach. Using ligand-and structure-based modelling combined with MD simulations (which identified Val 84 displacement as a novel conformational descriptor of A 2A R activation), a series of known PDE10A inhibitors were shown to dock to the orthosteric site of the A 2A R. Subsequent in-vitro analysis confirmed that these compounds bind to the A 2A R and exhibit dual-activity at both the A 2A R and PDE10A. Furthermore, many of the compounds exhibited promising anti-proliferative effects upon NSCLC cell-lines, which directly correlated with the expression of both PDE10A and the A 2A R. Thus, we propose a structure-based methodology, which has been validated in in-vitro binding and functional assays, and demonstrated a promising therapeutic value.
... In addition, and in accordance with the concept described above, calcium (Ca 2+ ) channel blockers (CCBs), medicines typically prescribed for treating hypertension, have been demonstrating anti-cancer effects [6][7][8]. A possible mechanism of action could rest in the fact that these pharmaceuticals may restore the dysregulation of Ca 2+ homeostasis [9][10][11][12][13]. Furthermore, the phenomenon entitled as ´calcium paradox´, which has been elucidated by us in 2013, has also been associated with the CCBs [14]. ...
... In this arena, endoplasmic reticulum (ER) Ca 2+ channels have particularly been a vanguard for the field, such as ryanodine receptors (RyR) [18][19][20][21][22][23][24][25]. Through our studies, we have recognized that the Ca 2+ /cAMP signaling performance an essential role in: controlling the neurotransmitter release from neurons, and neuroendocrine cells, including modulating the neuronal death [18][19][20][21], and in the development of cancer [9][10][11][12][13]. ...
... These findings suggest that the cAMP analogs, such as 8-Cl-cAMP and the PKA -selective cAMP analogs, could be used in human tumor therapy. Thus, considering that our studies have shown that the reduction of Ca 2+ influx through L-type Ca 2+ channels, produced by CCBs, increases the AC activity (and consequently elevating cAMP levels; named as Ca 2+ /cAMP signaling interaction) [9][10][11][12][13], and that these CCBs-effects can be potentiated by cAMP-stimulating compounds (like PDEs inhibitors), then the pharmacological modulation of the Ca 2+ /cAMP signaling could be a new therapeutic strategy for the tumor therapy. In addition, our discovery, which demonstrated the role of Ca 2+ /cAMP signaling in the neurotransmitter release and neuroprotection [18][19][20][21], may put some new ´light´ in the association between hypertension and higher risk for the development of cancer! ...
The incidence of cancer and hypertension is dramatically increasing in worldwide population, costing millions and millions from governments into expenditures related to the medical health systems. Interestingly, hypertension has been clinically linked to an increased risk for developing cancer. However, the mechanisms involved in this possible link are still under intensive debate. In addition, a Ca2+ homeostasis dysregulation has been intensively debated as an issue involved in both cancer and hypertension. Furthermore, calcium (Ca2+) channel blockers (CCBs), prescribed for treating hypertension, have been showing anti-cancer effects beyond their property of reducing blood pressure. A debated mechanism of action could rest in the fact that CCBs may maintain, or restore, the Ca2+ homeostasis. Our discovery entitled "calcium paradox" due to the Ca2+ /cAMP signaling may put some new light in this arena! Then, in this short communication, I have debated the possible involvement of the Ca2+ /cAMP signaling in the anti-cancer effects of CCBs, including a role of the Ca2+ /cAMP signaling in the clinical link between hypertension and higher risk for the development of cancer.
... In response to the reduction of Ca 2+ influx through plasma membrane voltage-activated Ca 2+ channels (L) produced Several evidences support that the abnormal intracellular signaling mediated by Ca 2+ and cAMP could be involved in tumor growth and dissemination [31][32][33][34][35][36][37]. As previously mentioned, the abnormal gene expression and activity of the different proteins involved intracellular Ca 2+ homeostasis contribute to tumor growth [14][15][16][17][18]. ...
... In addition, the increase of [cAMP] c inhibits the angiogenesis and tumor growth [21][22][23][24]. Thus, we have proposed that the combined use of monoclonal antibodies with drugs that modulate the Ca 2+ /cAMP signaling interaction to reduce tumor growth could be potential strategy in the antitumor immunotherapy due to increment of antitumor efficacy and reduction of adverse effects [31][32][33][34][35][36][37]. Figure 1 shows how the Ca 2+ /cAMP signaling interaction could be pharmacologically modulated by the combined use of the Ca 2+ channel blockers (CCB) and drugs that promote the increase of [cAMP] c (cAMP-enhancer compounds). ...
... Several evidences suggest that the cytosolic Ca 2+ overload due to abnormal gene expression and activity of the different types of Ca 2+ channels importantly contribute to tumor growth and dissemination due to cytosolic Ca 2+ overload in tumor cells [14][15][16][17][18]. Evidences suggest that Ca 2+ channels TRP and Orai participate in the intracellular Ca 2+ signaling involved the physiological angiogenesis processes [17]. Thus, the Ca 2+ channels have become important molecular targets in tumor cells and the drugs that interfere with the Ca 2+ channels could be useful in the treatment of different types of tumor [18,[31][32][33][34][35][36][37]40,41]. ...
Cancer is a major public health problem and the second leading cause of mortality around the world. Antitumor immunotherapy using monoclonal antibodies is considered selective and efficient in the treatment of different types of tumors, but its cost and toxic effects limit its application. Many tumor microenvironments, including lymphoma and carcinoma, are enriched in immune suppressive cells that contribute to immune exhaustion by means expression of inhibitory ligands, suppressive cytokines, and tumor-promoting factors. Antitumor therapies targeted to reduce the induction, recruitment, or suppressive activities of the immune cells have been investigated. New antitumor strategies using drugs targeted to intracellular signaling involved in cell proliferation and survival, angiogenesis, and metastasis have become promising in recent years. Thus, our discovery of the role of functional interaction between intracellular signaling pathways mediated by calcium ions (Ca 2+) and cyclic adenosine monophosphate (cAMP) (Ca 2+ /cAMP signaling interaction) in these cellular responses, opened a great avenue for the development of new antitumor therapeutic strategies. Here, we discuss how the combined use of monoclonal antibodies with drugs that modulate the Ca 2+ /cAMP signaling interaction to reduce tumor growth could be a potential strategy in the antitumor immunotherapy due to the increment of antitumor efficacy and reduction of adverse effects.
... Intracellular levels of Ca 2+ are regulated by plasma membrane transporters that control the influx, and efflux of Ca 2+ . Organelles, such as endo/sarcoplasmic reticulum, and Golgi complex, also regulate the intracellular levels of Ca 2+ [8]. Since tumor cells preferentially produce energy by anaerobic glycolysis in detrimental of mitochondrial oxidative phosphorylation process, it is necessary to pump larger amounts of Ca 2+ into the intracellular compartment [9]. ...
... 2017 | Volume 2 | Issue 1 2 may be associated with alterations in the regulation of the Ca 2+ and cAMP signaling pathways [15], and different tumors are associated with the Ras mediated signaling pathway [16,17]. Once the use of Ca 2+ channels blockers [18] and phosphodiesterase inhibitors (alone or in combination with other drugs) [19,20] for the treatment of cancer presents significant pre-clinical results, our proposal is to pharmacologically modulate the intracellular levels of Ca 2+ and cAMP signaling pathways in tumor cells [8], pathways that are altered in relation to healthy cells. Thus, we believe that combining this new strategy of treatment with existing antitumoral therapies may lead to reduce tumor progression, toxicity and costs of treatment. ...
... Ca2+/cAMP intracellular signaling interaction Calcium (Ca2+) is an intracellular second messenger stored inside the endoplasmic reticulum and mitochondria [5,6]. The intracellular Ca2+ flow is regulated by different channels and transporters, such as the receptor of inositol-1,4,5-triphosphate (IP3R) and Ca2+-ATPase pump [7]. The passage of Ca2+ by the plasma membrane can occur through voltageactivated Ca2+ channels (Cav family) and through transient receptor potential channels (TRPs). ...
... In addition to Ca2+, cyclic adenosine cyclic nucleoside monophosphate (cAMP) acts as an intracellular signal transducer mediating extracellular signaling to the cytoplasm. The cAMP can directly regulate the activation of ion channels, and indirectly the gene exression, differentiation and cellular growth [7]. ...
This editorial highlights the relevance of interfering in cancer cell progression through the pharmacological manipulation on the cell metabolism of cyclic nucleotides such as cAMP, and on the intracellular Ca2+ signaling, which may avail the reduction of toxic effects promoted by chemotherapy, radiotherapy and immunotherapy, thus decreasing the incidence of interruption in antitumoral treatment.
Pacientes oncológicos, geralmente, são submetidos a tratamentos quimioterápicos e radioterápicos, os quais tendem a causar problemas relacionados a intensos processos inflamatórios, de desnutrição, náuseas e êmese. Por isso, realizar a suplementação nestes pacientes é importante e necessário, pois isso favorece o paciente oncológico sob o ponto de vista nutricional. Estudos demonstram que a suplementação com β-glucanas promove benefícios aos pacientes oncológicos submetidos às quimioterapias e radioterapias. Os aminoácidos e β-glucanas obtidos a partir de processos de fermentação se mostraram importantes no cuidado de pacientes oncológicos, porque melhora os parâmetros nutricionais e estado geral do paciente. Assim, este trabalho objetiva discutir os benefícios obtidos pelos pacientes oncológicos submetidos às quimioterapias e radioterapias que receberam suplementação com um nutracêutico fermentado rico em β-glucanas e aminoácidos. A realização da revisão da literatura que foi feita pela busca ativa de artigos científicos através da utilização dos seguintes descritores em português: β-glucanas, aminoácidos, pacientes oncológicos, quimioterapia e radioterapia. Além disso, discutimos também os benefícios causados pela utilização do produto denominado de Bionutri AR1®, nutracêutico que contribui para a recuperação do estado nutricional, indicado para pacientes com desnutrição grave induzida pelo câncer e as abordagens terapêuticas quimioterapia e radioterapia. Concluímos que a utilização de produtos capazes de promover suplementação de β-glucanas e aminoácidos é extremamente benéfica aos pacientes oncológicos, principalmente, aos submetidos às quimioterapia e radioterapia e, por isso, há indicação de suplementação para esses pacientes com o produto fermentado Bionutri AR1®.
Background
The hypothesis that hypertension is clinically associated with an enhanced risk for developing cancer has been highlighted. However, the working principles involved in this link are still under intensive discussion. A correlation among inflammation, hypertension, and cancer could accurately describe the clinical link between these diseases. In addition, a dyshomeostasis of Ca2+ has been considered as a topic involved in both cancer and hypertension and inflammation. There is a strong link between Ca2+ signalling, e.g. enhanced Ca2+ signals, and inflammatory outcomes. cAMP also modulates pro- and anti-inflammatory outcomes: pharmaceuticals, which increase intracellular cAMP levels, can decrease the production of proinflammatory mediators and enhance the production of anti-inflammatory outcomes.
Objective
This article has discussed the participation of Ca2+/cAMP signalling in the clinical association among inflammation, hypertension, and an enhanced risk for the development of cancer. In addition, considering coronavirus disease 2019 (COVID-19) is a rapidly evolving field, this article also reviews recent reports about the role of Ca2+ channel blockers for restoring Ca2+ signalling disruption due to COVID-19, including the relationship among COVID-19, cancer, and hypertension.
Conclusion
Understanding the association among these diseases could expand current pharmacotherapy, including that involving Ca2+ channel blockers and pharmaceuticals which rise cAMP levels.
The incidence of both cancer and diabetes is dramatically increasing in worldwide population, costing many millions from governments into expenditures related to medical health systems. Diabetes has been clinically linked to an increased risk for developing several types of cancer. The cellular mechanisms involved in this link are still under intensive debate in literature. In addition, a Ca2+ homeostasis dysregulation has been intensively debated as an issue involved in both cancer and diabetes. Calcium (Ca2+) channel blockers (CCBs), prescribed for treating hypertension, have also been showing anti-cancer effects along with reducing diabetes symptoms. A debated mechanism of action could rest in the fact that CCBs may restore Ca2+ homeostasis dysregulations, involved in both diseases. Our studies about Ca2+/cAMP signalling may add some new light in this field. In this review, I have debated the possible involvement of Ca2+/cAMP signalling in the clinical link between diabetes and a higher risk for the development of several types of cancer, including the plausible involvement in both anti-cancer and anti-diabetic effects of CCBs.
