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The Second Messengers Ca2+ and cAMP as Potential Therapeutic Targets for the Control of Cancer Progression

  • July 2017
DOI:10.4172/2472-0429.1000e105
Authors:
Paolo Ruggero Errante at Universidade Federal de São Paulo
Paolo Ruggero Errante
Francisco Sandro Menezes Rodrigues at Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brazil
Francisco Sandro Menezes Rodrigues
  • Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brazil
Alberto Andrade Leite at Universidade Federal de São Paulo
Alberto Andrade Leite
Afonso Caricati-neto at Universidade Federal de São Paulo - Escola Paulista de Medicina, Brazil
Afonso Caricati-neto
  • Universidade Federal de São Paulo - Escola Paulista de Medicina, Brazil
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Abstract

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.
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The Second Messengers Ca2+ and camp as Potential Therapeutic Targets for the
Control of Cancer Progression
Paolo Ruggero Errante, Francisco Sandro Menezes-Rodrigues, Alberto Andrade Leite, Afonso Caricati-Neto and Leandro Bueno Bergantin*
Department of Pharmacology, Federal University of São Paulo-Paulista School of Medicine, Laboratory of Autonomic and Cardiovascular Pharmacology, Rua Pedro de
Toledo669 - Vila Clementino, São Paulo-SP, Brazil
Received date: July 2, 2017; Accepted date: July 5, 2017; Published date: July 15, 2017
*Corresponding author: Leandro Bueno Bergantin, Department of Pharmacology, Federal University of São Paulo-Paulista School of Medicine, Laboratory of
Autonomic and Cardiovascular Pharmacology, Rua Pedro de Toledo669 - Vila Clementino, São Paulo - SP, Brazil, Tel: 55 11 5576-4973; E-mail:
leanbio39@yahoo.com.br
Copyright: © 2017 Errante PR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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.
Keywords:
Cancer progression; Ca2+ channels blockers; Second messenger; Cyclic adenosine monophosphate, Ca2+/
cAMP interaction
Introduction
Cancer is an important cause of morbidity and mortality worldwide,
leading to the rise of great economic costs in the diagnosis and
treatment [1]. Despite the great scientic advances regarding the
tracking of tumor cells by liquid biopsy [2], interventions on tumors
are still limited to surgery, chemotherapy, radiotherapy and
immunotherapy [3]. Many patients discontinue the treatment because
of the great number of toxic and adverse eects promoted by
antitumor therapy. is interruption, or discontinuation, of treatment
may lead to cancer progression beyond the development of new
mutations, limiting therapeutic success, decreasing the overall quality
of life, or leading to early death of patients [4]. Our proposal consists in
the use of Ca2+ channel blockers and/or enhancers of cAMP synthesis
for the control of tumor growth to reduce the adverse eects and the
abandonment rate in dierent antitumor protocols.
Ca2+/cAMP intracellular signaling interaction Calcium (Ca2+) is
an intracellular second messenger stored inside the endoplasmic
reticulum and mitochondria [5,6]. e intracellular Ca2+ ow is
regulated by dierent channels and transporters, such as the receptor
of inositol-1,4,5-triphosphate (IP3R) and Ca2+-ATPase pump [7]. e
passage of Ca2+ by the plasma membrane can occur through voltage-
activated Ca2+ channels (Cav family) and through transient receptor
potential channels (TRPs). Intracellular Ca2+ ow is regulated by
mitochondrial Ca2+ uniporter (MCU), Na+/Ca2+ exchanger (NCX)
and Ca2+-induced Ca2+ release (CICR) mechanism [8].
e process of cell proliferation depends on the control of
intracellular levels of Ca2+, regulated by membrane transporters and
regulators of intracellular ow. A greater amount of Ca2+ is required
by tumor cells in relation to healthy cells for progression in the cell
cycle, which ultimately depends on signaling molecules, such as cyclins
[9].
e transition from G1 phase to S phase (mitosis) is a
Ca2+signaling-dependent process, such as dependent on Ca2+
calmodulin (CaM) and CaMkinase II (CaMK). e CaM and CaMK
regulate cyclins A, D1 and E [10], and active proteins of nuclear factor
of activated T-cells (NFAT) family, leading to activation of Ca2+
channels. e NFAT transcription factor was described as relevant in
the process of tumor invasion and metastasis in breast cancer [11].
Numerous transporters of Ca2+, like members of Ca2+-ATPases
family such as SERCA, present altered expression of isoforms in
dierents tumors cells [12]. A change in the expression of TRP
channels [13], L-type calcium channel [14], and T-type Ca2+ channels
[15] were observed in tumors cells [16].
During the process of tumor dissemination, Ca2+ participates in the
invasion of healthy tissues by tumor cells with involvement of Ca2+
channels. us, intracellular signals mediated by abnormal
concentrations of cytosolic Ca2+ are important in the maintenance of
the growth, invasion and tumor metastasis. Inhibition of T-type
calcium channels by mibefradil [17] or NecroX-5 [18] can prevent the
process of metastasis in breast tumors.
In addition to Ca2+, cyclic adenosine cyclic nucleoside
monophosphate (cAMP) acts as an intracellular signal transducer
mediating extracellular signaling to the cytoplasm. e cAMP can
directly regulate the activation of ion channels, and indirectly the gene
exression, dierentiation and cellular growth [7].
e cAMP can interact with Ras-mediated MAP kinase and, upon
binding to cAMP-dependent kinases (PKA), is able to modulate cell
growth. is mechanism of intracellular signaling has been implicated
in dierent types of tumors [19], and the pharmacological
manipulation of cAMP may lead to the decrease of tumor progression
[20].
Advances in Cancer Prevention Errante et al., Adv Cancer Prev 2017, 2:2
DOI: 10.4172/2472-0429.1000e105
Editorial OMICS International
Adv Cancer Prev, an open access journal
ISSN:2472-0429
Volume 2 • Issue 2 • 1000e105
us, the pharmacology manipulation leading to decreased of
intracellular Ca2+ levels, and increasing of cAMP, can help to reduce
the development of the intrinsic resistance of the tumors by dierent
conventional antitumor protocols. en, we suggest that the
pharmacological control of the intracellular levels of Ca2+ and cAMP
may decrease the rate of tumor growth, invasion and metastasis. is
strategy, combined with conventional antitumor treatments, may help
reduce the dose of existing drugs in the treatment of tumors, reducing
the adverse eects and the rate of abandoned therapy.
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Citation: Errante PR, Rodrigues FSM, Leite AA, Caricati-Neto A, Bergantin LB (2017) The Second Messengers Ca2+ and camp as Potential
Therapeutic Targets for the Control of Cancer Progression. Adv Cancer Prev 2: e105. doi:10.4172/2472-0429.1000e105
Page 2 of 2
Adv Cancer Prev, an open access journal
ISSN:2472-0429
Volume 2 • Issue 2 • 1000e105
... 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! ...
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... 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]. ...
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... Isn't it spectacular? Thus, whether this interaction may be a novel therapeutic goal to alter cancer tumor growth, angiogenesis and metastasis, without affecting normal cell physiology deserves special reflection [18][19][20][21]. So, the current information about modulation of the homeostasis of Ca 2+ and cAMP in cancer tumor cells, and the search for new drugs to regulate these intracellular messengers, may be able to lead the progress (in the future) of novel pharmacological strategies that specifically alter tumor growth, angiogenesis and metastasis, possible without affecting normal cell physiology. ...
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Our group has been pioneering in exploring that the pharmacological handling of Ca 2+/ cAMP signalling interaction could be a better therapeutic method for increasing neurotransmission in psychiatric disorders, and stimulating neuroprotection for combating neurodegenerative diseases, such as Alzheimer´s disease. Indeed, Ca 2+ is a classic intracellular second messenger, now well recognized as a ubiquitous molecule that controls several processes, including gene transcription, cell cycle regulation, mobility, apoptosis, neurotransmitter release and muscle contraction. In addition, cAMP, another vital intracellular messenger, modulates since cardiac contraction to neurotransmitter release. Do these intracellular messengers´work´ independently? Of course not, and we demonstrated it! Through groundbreaking experiments (including one by accident!), our group discovered that the paradoxical effects (e.g. reduction of intracellular Ca 2+ concentration, and enhancing of neurotransmitter release?!) produced by L-type Ca 2+ channel blockers (CCBs) resulted from interferences on the Ca 2+ / cAMP signalling interaction. Considering the widely use of CCBs as antihypertensive drugs, and for combating arrhythmia, the elucidation of these paradoxical effects proved to be very important (specially for clinical reasons). How does this history correlate to cancer field? Considering the notion that Ca 2+ /cAMP signalling interaction is a fundamental cellular process, which exists in many cell types, whether this interaction may be a novel therapeutic target to alter cancer tumor growth, angiogenesis and metastasis, without affecting normal cell physiology deserves special consideration. Thus, this editorial article highlights the latest advances made by our group in the field of Ca 2+ /cAMP signalling interaction.
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  • Dec 2016
The intracellular calcium ions (Ca²⁺) act as second messenger to regulate gene transcription, cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca²⁺ homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis, progression and metastasis. Targeting derailed Ca²⁺ signaling for cancer therapy has become an emerging research area. This review summarizes some important Ca²⁺ channels, transporters and Ca²⁺-ATPases, which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca²⁺ channels/transporters or Ca²⁺-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for research into the understanding of cellular mechanisms underlying the regulation of Ca²⁺ signaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca²⁺ channels or transporters.
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Cost drivers for breast, lung, and colorectal cancer care in a commercially insured population over a six-month episode: an economic analysis from the payer perspective
Article
  • Jun 2017
Aims: In the absence of clinical data, accurate identification of cost drivers is needed for economic comparison in an alternate payment model. From a payer perspective using claims data in a commercial population, our objective was to identify and quantify the effects of cost drivers in economic models of breast, lung, and colorectal cancer costs over a six-month episode following initial chemotherapy. Research Design and Methods: We analyzed claims data from 9,748 Cigna beneficiaries with diagnosis of breast, lung, and colorectal cancer following initial chemotherapy from January 1, 2014 to December 31, 2015. We used multivariable regression models to quantify the impact of key factors on cost during the initial six-month cancer care episode. Results: Metastasis, facility provider affiliation, episode risk group (ERG) risk score, and radiation were cost drivers for all three types of cancer (breast, lung, and colorectal). In addition, younger age (p < 0.0001) and human epidermal growth factor receptor-2 oncogene overexpression (HER2+)-directed therapy (p < 0.0001) were associated with higher costs in breast cancer. Younger age (p < 0.0001) and female gender (p < 0.0001) were also associated with higher costs in colorectal cancer. Metastasis also was associated with 50% more hospital admissions and increased hospital length of stay (p <0.001) in all three cancers over the six-month episode duration. Chemotherapy and supportive drug therapies accounted for the highest proportion (48%) of total medical costs among beneficiaries observed. Conclusions: Value-based reimbursement models in oncology should appropriately account for key cost drivers. Although claims-based methodologies may be further augmented with clinical data, we recommend adjusting for the factors we identified in models to predict costs in breast, lung, and colorectal cancers.
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Rolipram potentiates bevacizumab-induced cell death in human glioblastoma stem-like cells
Article
  • Feb 2017
Aims: Glioblastoma cancer stem-like cells (GCSCs) promote themselves proliferation by secreting the vascular endothelial growth factor A (VEGFA) in an autocrine manner, positively regulated by phosphodiesterase IV (PDE4). In the current study, we investigated the putative cytotoxic effect of bevacizumab, a VEGFA blocker, alone and in combination with a specific inhibitor of PDE4 called rolipram on GCSCs isolated from human surgical tumor specimen with a focus on PI3K/AKT pathway. Main methods: CD133+/CD15+ GCSCs were characterized by flow cytometry and expanded in a serum-free primary culture system. The cell survival, apoptosis, and protein expression values were measured using MTT assay, TUNEL staining and western blot, successively. Intracellular cAMP and free secreted VEGFA levels were assessed by cAMP enzyme immunoassay and ELISA, respectively. Key findings: Bevacizumab suppressed GCSCs survival with IC50~6.5μg/ml and enhanced the levels of apoptosis, p53 and cleaved-caspase3 along with a decrease in free VEGFA levels and ERKs activation. However, there was no significant modulation of AKT phosphorylation on serine 473, the intracellular PDE4A, VEGFA and cAMP levels. More cytotoxicity in co-treated cells coupled with a more substantial decline in the free VEGFA levels and a greater increase in the quantities of p53 and cleaved-caspase3 compared to those treated with bevacizumab alone. Co-treatment reduced phospho-AKT, endogenous VEGFA and PDE4A values but elevated cAMP levels. Significance: This study highlighted a booster cytotoxic effect of combined rolipram and bevacizumab treatment on the GCSCs primary culture, suggesting that this approach is warranted in treatment of GBMs overexpressing VEGFA and PDE4A.
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Cobimetinib: inhibiting MEK1/2 in BRAF V600-mutant melanoma
Article
Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor cobimetinib. Recently, cobimetinib was approved for the treatment of metastatic or unresectable melanoma with serine/threonine-protein kinase B-raf (BRAF) V600E or V600K mutations when used in combination with the BRAF inhibitor vemurafenib. Currently, multiple clinical trials are investigating this drug combination for the treatment of various cancer types (e.g., breast, melanoma, colorectal). In the phase III coBRIM trial, this combination therapy showed improved melanoma response rates and patient progression-free survival when compared to vemurafenib alone. Additionally, toxicities were generally found to be manageable with dose modification or interruption. However, tumor response to BRAF/MEK inhibition, though rapid, is often short-lived as tumors develop resistance to this combination therapy. Therefore, new trials are beginning to investigate the addition of a third targeted agent or immunotherapy in order to increase the durability of treatment response. These trials are already showing promising preliminary results. Copyright © 2016 Prous Science, S.A.U. or its licensors. All rights reserved.
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NecroX-5 prevents breast cancer metastasis by AKT inhibition via reducing intracellular calcium levels
Article
  • Dec 2016
A major goal of breast cancer research is to prevent the molecular events that lead to tumour metastasis. It is well-established that both cytoplasmic and mitochondrial reactive oxygen species (ROS) play important roles in cell migration and metastasis. Accordingly, this study examined the molecular mechanisms of the anti-metastatic effects of NecroX-5, a mitochondrial ROS scavenger. NecroX-5 inhibited lung cancer metastasis by ameliorating migration in a mouse model. In human cancer cells, the inhibition of migration by NecroX-5 is cell type-dependent. We observed that the effect of NecroX-5 correlated with a reduction in mitochondrial ROS, but mitochondrial ROS reduction by MitoQ did not inhibit cell migration. NecroX-5 decreased intracellular calcium concentration by blocking Ca2+ influx, which mediated the inhibition of cell migration, AKT downregulation and the reduction of mitochondrial ROS levels. However, the reduction of mitochondrial ROS was not associated with supressed migration and AKT downregulation. Our study demonstrates the potential of NecroX-5 as an inhibitor of breast cancer metastasis.
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Calcium-ATPases: Gene disorders and dysregulation in cancer
Article
Ca(2+)-ATPases belonging to the superfamily of P-type pumps play an important role in maintaining low, nanomolar cytoplasmic Ca(2+) levels at rest and priming organellar stores, including the endoplasmic reticulum, Golgi and secretory vesicles with high levels of Ca(2+) for a wide range of signaling functions. In this review, we introduce the distinct subtypes of Ca(2+)-ATPases and their isoforms and splice variants, and provide an overview of their specific cellular roles as they relate to genetic disorders and cancer, with a particular emphasis on recent findings on the secretory pathway Ca(2+)-ATPases (SPCA). Mutations in human ATP2A2, ATP2C1 genes, encoding housekeeping isoforms of the endoplasmic reticulum (SERCA2) and secretory pathway (SPCA1) pumps respectively, confer autosomal dominant disorders of the skin, whereas mutations in other isoforms underlie various muscular, neurological or developmental disorders. Emerging evidence points to an important function of dysregulated Ca(2+)-ATPase expression in cancers of the breast, colon, lung and breast where they may serve as markers of differentiation or novel targets for therapeutic intervention. We review the mechanisms underlying the link between calcium homeostasis and cancer and discuss the potential clinical relevance of these observations. This article is part of a Special Issue entitled: Calcium and Cell Fate edited by Jacques Haiech, Claus Heizmann and Joachim Krebs.
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