New Antitumoral Pharmacological Strategies Involving Ca2+ /cAMP Signaling Pathways

Abstract

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+ and its Ca2+ channels, which are
functionally altered, or amplified, in different types of
cancer cells. Understanding these mechanisms is crucial
for knowledge of process of tumor progression, and for
the creation of new pharmacological strategies to control
the growth and spread of tumor cells. In this review, we
address the relevance of cyclic nucleotides such as cAMP,
and Ca2+ channels in tumor cells, emphasizing the
possibility of combined pharmacological interventions
which interfere with these intracellular signaling
pathways.

Full text

New Antumoral Pharmacological Strategies Involving Ca2+/Camp Signaling
Pathways
Ruggero Errante P, Menezes-Rodrigues FS, Alberto Andrade Leite, Afonso Caricati-Neto and
Leandro Bueno Bergantin
Department of Pharmacology, Laboratory of Autonomic and Cardiovascular Pharmacology, Federal University of São Paulo, Paulista Medical
School, Sao Paulo, Brazil
Corresponding author: Leandro Bueno Bergann, Department of Pharmacology, Federal University of São Paulo, Paulista Medical School,
Laboratory of Autonomic and Cardiovascular Pharmacology, Rua Pedro de Toledo, 669 Vila Clemenno, Sao Paulo, Brazil, Tel: 55115576-4973;
E-mail: leanbio39@yahoo.com.br
Received date: April 29, 2017; Accepted date: May 10, 2017; Published date: May 15, 2017
Citaon: Errante PR, Menezes-Rodrigues FS, Leite AA, et al. New Antumoral Pharmacological Strategies Involving Ca2+/Camp Signaling
Pathways. J Cancer Epidemiol Prev. 2017, 2:1.
Abstract
Cell signaling is a crucial event for the survival and
progress of normal cellular funcons. However, mutaons
of certain genes can lead to the emerging of cancer cells,
which can use these signaling mechanisms for their
survival, growth and disseminaon. Among these
mechanisms, we highlight the role of cyclic nucleodes
such as cAMP, and Ca2+ and its Ca2+ channels, which are
funconally altered, or amplied, in dierent types of
cancer cells. Understanding these mechanisms is crucial
for knowledge of process of tumor progression, and for
the creaon of new pharmacological strategies to control
the growth and spread of tumor cells. In this review, we
address the relevance of cyclic nucleodes such as cAMP,
and Ca2+ channels in tumor cells, emphasizing the
possibility of combined pharmacological intervenons
which interfere with these intracellular signaling
pathways.
Keywords: Cancer; Ca2+ channels; Ca2+ signaling; Cyclic
adenosine monophosphate; cAMP signaling
Introducon
Cell signaling is part of a communicaon process that
governs basic acvity of cell, and the ability of cell to respond
to the microenvironment. This mechanism is fundamental to
the homeostasis, ssue repair and control of malignance [1].
Errors in signaling interacon, and cellular informaon process
between cells, are responsible for dierent pathologies, such
as cancer. The development of cancer cells is associated with
the mutaon of four disnct groups of genes: the proto-
oncogenes growth promoters [2]; tumor suppressor genes [3];
genes that regulate genecally programmed cell death
(apoptosis) and genes involved in DNA repair [4]. The
abnormal cell division causes cancer, also called as
carcinogenesis, and may be associated with exposure to
chemicals, radiaon [5] or microbial agents, especially viruses
[6].
Carcinogenesis is a mul-step process resulng from the
accumulaon of mulple mutaons that accumulate
independently in dierent cell types, generang subclones
with dierent characteriscs. These characteriscs make the
tumors have capacity for invasion and metastasis, rapid growth
speed, hormone response and resistance to anneoplasc
drugs [7,8]. Numerous normal biochemical mechanisms may
be altered, leading to the emergence of these disnct
characteriscs of cancer cells. Among these several altered
biochemical characteriscs, the change in the behavior of
inux, and eux, of intracellular Ca2+, and the signaling
mediated by cyclic nucleodes i.e., cAMP can be veried. Since
intracellular signaling measured by calcium and cyclic
nucleodes is a canonical event, changes in this signaling
pathway are crucial for the survival and growth of cancer cells
[9]. In this way, the knowledge of cancer physiology is crucial
to the development of new strategies to control the growth,
disseminaon and metastasis. In this arcle, the involvement
of Ca2+ channels, and cyclical nucleodes like cAMP in cancer
development and progression, and the use of new
pharmacological strategies with potenal capacity of control
the cancer growth, and progression are discussed.
Cyclical nucleodes in cancer cells
The nucleodes are composed by a nitrogenous base, a
pentose and one or more phosphate groups, and parcipate of
numerous intracellular biochemical processes. They act as
precursors of deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA), energy source (adenosine triphosphate and guanosine
triphosphate), coenzymes (avin adenine dinucleode,
niconamide adenine dinucleode and coenzyme A) and
physiological regulators (cyclic adenosine monophosphate and
cyclic guanosine monophosphate) [10]. The cyclic adenosine
monophosphate (cAMP) is a second messenger that acts as
intracellular signal transducon leading to a cAMP-dependent
pathway. The cAMP is synthesized from ATP by the adenylyl
cyclase located on the inner side of the plasma membrane.
Review Article
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Adenylyl cyclase is acvated by signaling molecules through
the acvaon of receptors with the G-protein smulatory (Gs)
of adenylyl cyclase, and inhibited by inhibitory G (G) receptor
agonists of adenylyl cyclase [11]. When cAMP concentraon
increases (acvaon of the adenylate cyclases by the Gs
protein, and inhibion of cAMP-degrading
phosphodiesterases), cAMP binds to the regulatory subunits,
which leads to the release of the catalyc subunits. The free
catalyc subunits catalyze the transfer of terminal phosphates
from ATP [12]. The link between membrane surface of cell and
cytoplasm is mediated by a family of enzymes called kinase
proteins dependent of cAMP, or protein kinase A (PKA), by
transformaon of ATP in ADP with phosphorylaon of protein
substrates responsible by intracellular eects [13].
Mechanisms involving the control of cAMP over PKA can be
divided into: direct protein phosphorylaon and protein
synthesis. In direct phosphorylaon, PKA both increases and
decreases the acvity of a protein; and in protein synthesis
PKA rst acvates the cAMP response element-binding protein
(CREB), a cellular transcripon factor, which binds to the cAMP
response element, altering transcripon and protein synthesis
[14]. In the negave regulaon of PKA, one of the substrates
acvated by kinase is a phosphodiesterase, which converts
cAMP to AMP, reducing the amount of cAMP that can acvate
PKA. The catalyc funcon of PKA can be combined with A-
kinase anchoring proteins (AKAP). AKAP are signal-organizing
molecules that compartmentalize various enzymes that are
regulated by second messengers. PKA binding with AKAP, and
a phosphodiesterase, form a complex that hydrolyzes cAMP.
Considering the phosphodiesterase contributes to the low
concentraon of cAMP in cells, PKA is responsible for the
acvaon of phosphodiesterase, to lower the concentraon of
cAMP [11]. The cyclic nucleodes, cyclic adenosine
monophosphate (cAMP) and cyclic guanosine monophosphate
(cGMP), are important intracellular signal transducon
molecules, acng as second messengers through an
extracellular signal. Both cAMP and cGMP signaling have
posive or negave eects on growth and survival, depending
on the type cell. The cAMP can regulate a variety of cellular
funcons: metabolism of ion channel acvaon, cell growth
and dierenaon, gene expression and apoptosis [15]. The
cAMP pathway acts with other intracellular signaling pathways
such as those mediated by Ca2+ [16], and Jak/STAT [17]. The
cAMP interacts with Ras-mediated MAP kinase, modulang
cell growth [18] when binding to cAMP-dependent protein
kinases (PKA) [19]. When acvated, PKA phosphorylates
macromolecular complexes responsible for the destrucon of
mitoc cyclins, and separaon of sister chromads in the
anaphase-metaphase transion [20]. The involvement of
cAMP, and the acvaon of PKA, has been associated with
dierent types of cancer [21], where oncogenic acvity of
cAMP is due to the acvaon of PKA, and downstream
eectors (exchange protein directly acvated by cAMP (Epac)
and CREB) [22].
The PKA-mediated cascade is required for the funconal
regulaon of D-type cyclins, so defects in the cAMP/PKA
pathway can induce tumors in cell lines [23], which can be
reversed by modifying the PKA subunit type that is expressed
by the cell. The circuity formed by PKA, and cAMP, can
inuence the growth of colorectal cancer cell by decreasing
cAMP intracellular levels [24]. Any tumors present a
predominant of determined forms of PKA, such as
glioblastoma, with predomin of PKA type II [25]. In the same
way, the increase of cAMP levels can diminish the tumor
growth [26]. Other funcon, in which PKA may be
dysregulated in cancer, is the cell migraon that involves
cytoskeleton remodeling [27].
Numerous mutaons lead to the formaon of oncogenes
that encode dierent protein kinases. Changes in the acvity
of protein kinases alter numerous signaling pathways, such as
those involved in the cytosolic concentraon of Ca2+.
Intracellular signals mediated by abnormal cytosolic Ca2+
concentraons are important in maintenance, growth,
inavasion and metastasis by cancer cells.
Ca2+ signaling and channels in cancer cells
The Ca2+ acts as an important intracellular messenger
because it is a bivalent molecule that has strong and specic
binding to it receptor, and has an atomic radius that gives it
ideal geometry for protein binding [28]. Usually, Ca2+ is stored
in specic organelles, such as endoplasmic reculum and
mitochondria [9]. Indeed, intracellular Ca2+ homeostasis is
regulated by numerous channels and transporters of Ca2+, for
example by the receptor of inositol-1,4,5-triphosphate (IP3R)
and Ca2+-ATPase pump [for example plasma membrane Ca2+-
ATPase (PMCA), ER/SR Ca2+-ATPase (SERCA), and golgi vesicles
secretory pathway Ca2+-ATPase (SPCA)]. In addion, the Ca2+
inux across plasma membrane occurs through voltage-
acvated Ca2+ channels (VACCs, also known as Cav family) and
transient receptor potenal channels (TRPs). Intracellular Ca2+
homeostasis is also regulated by the Ca2+-induced Ca2+ release
(CICR) mechanism, Na+/Ca2+ exchanger (NCX) and
mitochondrial Ca2+ uniporter (MCU) [29].
The release of Ca2+ from the endoplasmic reculum to the
cytoplasm is performed through classical signalling pathways,
acvated by specic agonists and receptors, located in the
surface of plasma membrane, for example by acvang
phospholipase C, it hydrolyzes phosphadylinositol 4,5-
bisphosphate (PIP2) of plasma membrane, so producing
inositol-1,4,5-triphosphate (IP3). The diusion of IP3 into the
cell releases intracellular Ca2+ of their stocks by the acvaon
of specic receptors (IP3R), which are localized in the
cytoplasmic side of endoplasmic reculum membrane [30].
The increase of expression, or acvity, of Ca2+ channels in the
plasma membrane leads to increase of Ca2+ inux, promong
Ca2+-dependent cell proliferaon and dierenaon [31].
These mechanisms of inux, and eux, of intracellular Ca2+
are dependent on Ca2+ transporters located mostly in the
plasma membrane. Several Ca2+ channels, like Ca2+-dependent
voltage channels, are involved in the Ca2+ inux. However,
these channels require depolarizaon of the plasma
membrane, being more common on the surface of excitable
cells, as cardiomyocytes [32]. Some of these Ca2+ channels, are
members of the Cav3 subfamily acvated by low voltage, are
expressed on the surface of dierent cancerous cells [33], and
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Ca2+ entry in non-excitable cells mostly occurs through non-
voltage gated channels.
The non-voltage gated channels of Ca2+ associated with
dierent types of cancer cells include: ligand-gated channels;
receptor-operated channels (ROC) or secondary messenger-
operated channels linked to GPCR acvaon [SMOC: Orai
family and members of TRP (Transient Receptor Potenal)
superfamily of channels]; store-operated channels (SOCE: Orai
family and members of TRPC (TRP Canonical) subfamily of
channels); and stretch-operated channels (members of TRP
superfamily of channels); plasma membrane Ca2+-ATPase
(PMCA); and Na+/Ca2+ exchanger [34].
Cellular proliferaon depends on the cell cycle, which is
dependent on Ca2+. Cell proliferaon, and cell division, depend
on extracellular Ca2+, and the increase in intracellular Ca2+ is
involved in cell cycle progression, and proliferaon [35]. The
Ca2+ is required at the beginning of the G1 phase of the cell
cycle, where acvaon of transcripon factors like acvator
protein 1 (AP1), a transcripon factor that regulates gene
expression, and cellular processes dierenaon,
proliferaon, and apoptosis; cAMP-responsive element
binding protein (CREB) and the nuclear factor of acvated T-
cell (NFAT) [36].
The Ca2+ plays a key role in the expression of cell cycle
regulators like the D-type cyclins, required for the acvaon of
cyclin-dependent kinase 4 complexes, responsible of
phosphorylaon and inacvaon of renoblastoma gene,
involved in the entry into S phase of cell cycle. The start of
G1/S phase is dependent of Ca2+ calmodulin (CaM), and
CaMkinase II (CaMK) [37]. Calcineurin, a Ca2+-dependent
phosphatase, plays a major role in progression of G1 and S
phases, regulang cyclins A, D1 and E [37,38] and acve NFAT,
favoring the cell proliferaon, through the acvaon of Ca2+
channels. The IP3Rs are the major channels of intracellular
Ca2+ release in non-excitable cells, being acvated in dierent
types of cancer, such as gastric and colorectal cancer [39,40].
Making part of the Ca2+-ATPases family, SERCA presents an
altered expression in diferents cancers cells such as colon,
gastric, lung, myeloid leukaemia and choroid plexus [41].
Altered expression of SPCA isoforms are expressed in breast,
colon and prostate cancer [42], and altered expression of
PMCA isoforms are expressed in breast cancer cells [43].
The non-voltage gated channels of Ca2+, Orai and stromal
interacon molecule 1 (STIM1), a Ca2+ sensor in the
endoplasmic reculum, present higher expression in
glioblastoma [44], pancreac adenocarcinoma [45], prostate
cancer [46] and hepatocellular carcinoma [47]. The MCU is
overexpressed in breast cancer cells [48]. Changes in
expression of TRP channels, like TRPV1, TRPV2, TRPV6, TRPM8,
TRPM2, TRPC6 [34], L-type calcium channel [49], and T-type
Ca2+ channels [50,51] were observed in prostate cancer cells.
Also, the expression of TRP channels TRPC1, TRPC3, TRPC6,
TRPM7, TRPM8, and TRPV6 is altered in breast cancer [52],
thyroid, colon and ovary cancer, with emphasis of TRPV6
[53,54]. In lung cancer cells the expression of TRPC1, TRPC3,
TRPC4, TRPC6, TRPM7, and TRPM8 is altered [55]. During the
process of metastasis, Ca2+ parciples of invasion of health
ssues by cancer cells, with involvement of voltage
independent Ca2+ channels [56-58] in breast [59,60] and lung
cancer cell [61].
Potenal use of modulators of cyclical
nucleodes or inhibitors of Ca2+ channels
The growing understanding of cancer biology has led to the
development of new drugs for the treatment of cancer.
However, a total benecial eect of these agents has not yet
been veried by the presence of intrinsic cancer cell
resistance, the result of compensatory signaling pathways, or
the development of acquired resistance through the evoluon
of cell clones by selecve treatment pressures.
Recognizing the toxicity induced by the treatment and the
inability to use high eecve pharmacological doses in the
treatment of cancer, we are exploring the combinaon of Ca2+
channel blockers and/or enhancer agents of cAMP, associated
with chemotherapy, radiotherapy or immunotherapy.
Variaons in expression of Ca2+ channels in cell cancer
suggest that a decrease in Ca2+ channel expression, or Ca2+
inux, will lead to cell cycle arrest, inhibing the process of
invasion, metastasis, and recurrence of cancer. We also believe
that increasing the cytosolic concentraon of cAMP produced
by the drug combinaon could simultaneously generate
acvaon of the RAS (antumor) mediated signaling pathway,
and inhibion of the PKA (pro-tumor) pathway, favoring the
host.
For example, new treatments of cancer involving the use of
monoclonal anbodies against programmed death 1 (PD-1)
receptor, and its PD-L1 ligand [62], presented promising
results. PD-L1 is expressed in dierent types of cancer cells,
such melanoma, lung, breast, ovaries, pancreas, esophagus,
bladder and haematological tumors [63]. However, in spite of
the posive results observed with the use of monoclonal
anbodies against PD-L1/PD-1, recent studies have revealed
an aggressive growth of tumors in a small poron of paents
[64,65]. This process of tumor progression aer
immunotherapy has been described as being associated with
amplicaon of MDM2/MDM4 genes [65]. The MDM2/MDM4
genes inhibit the p53 tumor suppressor gene [66]. Normally
p53 is acvated in response to DNA damage, or oncogene
acvaon, which in turn starts mechanisms of apoptosis, cell-
cycle arrest or modulaon of autophagy.
Monoclonal anbodies against PD-1 can induce the increase
synthesis of interferon gamma (IFN-γ) by T lymphocytes [67],
which in turn acvates JAK-STAT signaling [68] resulng 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.
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Figure 1 A. Monoclonal anbodies 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 amplicaon 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
producon of IFN-γ, expression of IRF8 and MDM2
amplicaon. In turn, not occurring suppression of p53, or
tumor growth and progression. APC=Angen presenng
cell; MHC=Major histocompability complex;
mAB=Monoclonal anbody. B. Increase in the expression of
MDM2.
Because the elevaon of intracellular cAMP creates an
oxidave environment that oxidizes and inacvates p56(lck) in
lymphocytes by an H2O2 dependent, PKA-independent
mechanism, and inhibits the producon 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 producon of IFN-γ, which would
make dicult to increase the expression of IRF8, and increase
in the expression of MDM2 shown in Figure 1B.
Thus, the combinaon of a phosphodiesterase inhibitor with
an-PD-1 monoclonal anbodies could prevent the emerging
of new more aggressive tumor subclones.
This new pharmacological strategy could be extended not
only for the use of modulators of cAMP, but also for inhibitors
of Ca2+ channels. For example, it was described that the use of
inhibitor of Ca2+-dependent K+ channels (TRAM-34) is able to
block the growth of hepatocellular carcinoma [73]. Thus, the
use of TRAM-34 may be associated with hepac intra-arterial
chemotherapy, allowing a minor concentraon of the
chemotherapeuc oxuridine [74] in the liver with a lower
systemic toxic eect to the treatment of hepac
adenocarcinoma, primary or metastac. Because the
relevance of Orai1 and TRP channels in tumor
neovascularizaon [75], blockers of these channels can
diminish the adverses eects of treatment with ramucirumab,
a monoclonal anbodies against vascular endotelial growth
factor receptor 2 (VEGFR2), with an-angiogenic eect used to
the treatment of advanced gastric, gastro-oesophageal
juncon adenocarcinoma and non-small cell lung cancer
(NSCLC), with the possibility of decreased toxicity, and
adverses eects like neutropenia, febrile neutropenia and
hypertension [76].
Conclusion
Thus, the use of modiers of cAMP producon may
decrease the chance of developing intrinsic an-tumor
resistance, and the use of Ca2+ channel blockers may modify
tumor growth, and also by reducing the adverse eects of
chemotherapy, or immunotherapy.
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