New Antumoral Pharmacological Strategies Involving Ca2+/Camp Signaling
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 Bergann, Department of Pharmacology, Federal University of São Paulo, Paulista Medical School,
Laboratory of Autonomic and Cardiovascular Pharmacology, Rua Pedro de Toledo, 669 Vila Clemenno, Sao Paulo, Brazil, Tel: 55115576-4973;
Received date: April 29, 2017; Accepted date: May 10, 2017; Published date: May 15, 2017
Citaon: Errante PR, Menezes-Rodrigues FS, Leite AA, et al. New Antumoral Pharmacological Strategies Involving Ca2+/Camp Signaling
Pathways. J Cancer Epidemiol Prev. 2017, 2:1.
Cell signaling is a crucial event for the survival and
progress of normal cellular funcons. However, mutaons
of certain genes can lead to the emerging of cancer cells,
which can use these signaling mechanisms for their
survival, growth and disseminaon. Among these
mechanisms, we highlight the role of cyclic nucleodes
such as cAMP, and Ca2+ and its Ca2+ channels, which are
funconally altered, or amplied, in dierent types of
cancer cells. Understanding these mechanisms is crucial
for knowledge of process of tumor progression, and for
the creaon of new pharmacological strategies to control
the growth and spread of tumor cells. In this review, we
address the relevance of cyclic nucleodes such as cAMP,
and Ca2+ channels in tumor cells, emphasizing the
possibility of combined pharmacological intervenons
which interfere with these intracellular signaling
Keywords: Cancer; Ca2+ channels; Ca2+ signaling; Cyclic
adenosine monophosphate; cAMP signaling
Cell signaling is part of a communicaon process that
governs basic acvity 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 .
Errors in signaling interacon, and cellular informaon process
between cells, are responsible for dierent pathologies, such
as cancer. The development of cancer cells is associated with
the mutaon of four disnct groups of genes: the proto-
oncogenes growth promoters ; tumor suppressor genes ;
genes that regulate genecally programmed cell death
(apoptosis) and genes involved in DNA repair . The
abnormal cell division causes cancer, also called as
carcinogenesis, and may be associated with exposure to
chemicals, radiaon  or microbial agents, especially viruses
Carcinogenesis is a mul-step process resulng from the
accumulaon of mulple mutaons that accumulate
independently in dierent cell types, generang subclones
with dierent characteriscs. These characteriscs make the
tumors have capacity for invasion and metastasis, rapid growth
speed, hormone response and resistance to anneoplasc
drugs [7,8]. Numerous normal biochemical mechanisms may
be altered, leading to the emergence of these disnct
characteriscs of cancer cells. Among these several altered
biochemical characteriscs, the change in the behavior of
inux, and eux, of intracellular Ca2+, and the signaling
mediated by cyclic nucleodes i.e., cAMP can be veried. Since
intracellular signaling measured by calcium and cyclic
nucleodes is a canonical event, changes in this signaling
pathway are crucial for the survival and growth of cancer cells
. In this way, the knowledge of cancer physiology is crucial
to the development of new strategies to control the growth,
disseminaon and metastasis. In this arcle, the involvement
of Ca2+ channels, and cyclical nucleodes like cAMP in cancer
development and progression, and the use of new
pharmacological strategies with potenal capacity of control
the cancer growth, and progression are discussed.
Cyclical nucleodes in cancer cells
The nucleodes are composed by a nitrogenous base, a
pentose and one or more phosphate groups, and parcipate 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 dinucleode,
niconamide adenine dinucleode and coenzyme A) and
physiological regulators (cyclic adenosine monophosphate and
cyclic guanosine monophosphate) . The cyclic adenosine
monophosphate (cAMP) is a second messenger that acts as
intracellular signal transducon 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.
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Adenylyl cyclase is acvated by signaling molecules through
the acvaon of receptors with the G-protein smulatory (Gs)
of adenylyl cyclase, and inhibited by inhibitory G (G) receptor
agonists of adenylyl cyclase . When cAMP concentraon
increases (acvaon of the adenylate cyclases by the Gs
protein, and inhibion of cAMP-degrading
phosphodiesterases), cAMP binds to the regulatory subunits,
which leads to the release of the catalyc subunits. The free
catalyc subunits catalyze the transfer of terminal phosphates
from ATP . 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
transformaon of ATP in ADP with phosphorylaon of protein
substrates responsible by intracellular eects .
Mechanisms involving the control of cAMP over PKA can be
divided into: direct protein phosphorylaon and protein
synthesis. In direct phosphorylaon, PKA both increases and
decreases the acvity of a protein; and in protein synthesis
PKA rst acvates the cAMP response element-binding protein
(CREB), a cellular transcripon factor, which binds to the cAMP
response element, altering transcripon and protein synthesis
. In the negave regulaon of PKA, one of the substrates
acvated by kinase is a phosphodiesterase, which converts
cAMP to AMP, reducing the amount of cAMP that can acvate
PKA. The catalyc funcon 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
concentraon of cAMP in cells, PKA is responsible for the
acvaon of phosphodiesterase, to lower the concentraon of
cAMP . The cyclic nucleodes, cyclic adenosine
monophosphate (cAMP) and cyclic guanosine monophosphate
(cGMP), are important intracellular signal transducon
molecules, acng as second messengers through an
extracellular signal. Both cAMP and cGMP signaling have
posive or negave eects on growth and survival, depending
on the type cell. The cAMP can regulate a variety of cellular
funcons: metabolism of ion channel acvaon, cell growth
and dierenaon, gene expression and apoptosis . The
cAMP pathway acts with other intracellular signaling pathways
such as those mediated by Ca2+ , and Jak/STAT . The
cAMP interacts with Ras-mediated MAP kinase, modulang
cell growth  when binding to cAMP-dependent protein
kinases (PKA) . When acvated, PKA phosphorylates
macromolecular complexes responsible for the destrucon of
mitoc cyclins, and separaon of sister chromads in the
anaphase-metaphase transion . The involvement of
cAMP, and the acvaon of PKA, has been associated with
dierent types of cancer , where oncogenic acvity of
cAMP is due to the acvaon of PKA, and downstream
eectors (exchange protein directly acvated by cAMP (Epac)
and CREB) .
The PKA-mediated cascade is required for the funconal
regulaon of D-type cyclins, so defects in the cAMP/PKA
pathway can induce tumors in cell lines , which can be
reversed by modifying the PKA subunit type that is expressed
by the cell. The circuity formed by PKA, and cAMP, can
inuence the growth of colorectal cancer cell by decreasing
cAMP intracellular levels . Any tumors present a
predominant of determined forms of PKA, such as
glioblastoma, with predomin of PKA type II . In the same
way, the increase of cAMP levels can diminish the tumor
growth . Other funcon, in which PKA may be
dysregulated in cancer, is the cell migraon that involves
cytoskeleton remodeling .
Numerous mutaons lead to the formaon of oncogenes
that encode dierent protein kinases. Changes in the acvity
of protein kinases alter numerous signaling pathways, such as
those involved in the cytosolic concentraon of Ca2+.
Intracellular signals mediated by abnormal cytosolic Ca2+
concentraons 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 specic
binding to it receptor, and has an atomic radius that gives it
ideal geometry for protein binding . Usually, Ca2+ is stored
in specic organelles, such as endoplasmic reculum and
mitochondria . 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 addion, the Ca2+
inux across plasma membrane occurs through voltage-
acvated Ca2+ channels (VACCs, also known as Cav family) and
transient receptor potenal 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) .
The release of Ca2+ from the endoplasmic reculum to the
cytoplasm is performed through classical signalling pathways,
acvated by specic agonists and receptors, located in the
surface of plasma membrane, for example by acvang
phospholipase C, it hydrolyzes phosphadylinositol 4,5-
bisphosphate (PIP2) of plasma membrane, so producing
inositol-1,4,5-triphosphate (IP3). The diusion of IP3 into the
cell releases intracellular Ca2+ of their stocks by the acvaon
of specic receptors (IP3R), which are localized in the
cytoplasmic side of endoplasmic reculum membrane .
The increase of expression, or acvity, of Ca2+ channels in the
plasma membrane leads to increase of Ca2+ inux, promong
Ca2+-dependent cell proliferaon and dierenaon .
These mechanisms of inux, and eux, 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+ inux. However,
these channels require depolarizaon of the plasma
membrane, being more common on the surface of excitable
cells, as cardiomyocytes . Some of these Ca2+ channels, are
members of the Cav3 subfamily acvated by low voltage, are
expressed on the surface of dierent cancerous cells , 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
dierent types of cancer cells include: ligand-gated channels;
receptor-operated channels (ROC) or secondary messenger-
operated channels linked to GPCR acvaon [SMOC: Orai
family and members of TRP (Transient Receptor Potenal)
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 .
Cellular proliferaon depends on the cell cycle, which is
dependent on Ca2+. Cell proliferaon, and cell division, depend
on extracellular Ca2+, and the increase in intracellular Ca2+ is
involved in cell cycle progression, and proliferaon . The
Ca2+ is required at the beginning of the G1 phase of the cell
cycle, where acvaon of transcripon factors like acvator
protein 1 (AP1), a transcripon factor that regulates gene
expression, and cellular processes dierenaon,
proliferaon, and apoptosis; cAMP-responsive element
binding protein (CREB) and the nuclear factor of acvated T-
cell (NFAT) .
The Ca2+ plays a key role in the expression of cell cycle
regulators like the D-type cyclins, required for the acvaon of
cyclin-dependent kinase 4 complexes, responsible of
phosphorylaon and inacvaon of renoblastoma 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) . Calcineurin, a Ca2+-dependent
phosphatase, plays a major role in progression of G1 and S
phases, regulang cyclins A, D1 and E [37,38] and acve NFAT,
favoring the cell proliferaon, through the acvaon of Ca2+
channels. The IP3Rs are the major channels of intracellular
Ca2+ release in non-excitable cells, being acvated in dierent
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 .
Altered expression of SPCA isoforms are expressed in breast,
colon and prostate cancer , and altered expression of
PMCA isoforms are expressed in breast cancer cells .
The non-voltage gated channels of Ca2+, Orai and stromal
interacon molecule 1 (STIM1), a Ca2+ sensor in the
endoplasmic reculum, present higher expression in
glioblastoma , pancreac adenocarcinoma , prostate
cancer  and hepatocellular carcinoma . The MCU is
overexpressed in breast cancer cells . Changes in
expression of TRP channels, like TRPV1, TRPV2, TRPV6, TRPM8,
TRPM2, TRPC6 , L-type calcium channel , 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 ,
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 . During the
process of metastasis, Ca2+ parciples 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 .
Potenal use of modulators of cyclical
nucleodes 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 benecial eect of these agents has not yet
been veried by the presence of intrinsic cancer cell
resistance, the result of compensatory signaling pathways, or
the development of acquired resistance through the evoluon
of cell clones by selecve treatment pressures.
Recognizing the toxicity induced by the treatment and the
inability to use high eecve pharmacological doses in the
treatment of cancer, we are exploring the combinaon of Ca2+
channel blockers and/or enhancer agents of cAMP, associated
with chemotherapy, radiotherapy or immunotherapy.
Variaons in expression of Ca2+ channels in cell cancer
suggest that a decrease in Ca2+ channel expression, or Ca2+
inux, will lead to cell cycle arrest, inhibing the process of
invasion, metastasis, and recurrence of cancer. We also believe
that increasing the cytosolic concentraon of cAMP produced
by the drug combinaon could simultaneously generate
acvaon of the RAS (antumor) mediated signaling pathway,
and inhibion of the PKA (pro-tumor) pathway, favoring the
For example, new treatments of cancer involving the use of
monoclonal anbodies against programmed death 1 (PD-1)
receptor, and its PD-L1 ligand , presented promising
results. PD-L1 is expressed in dierent types of cancer cells,
such melanoma, lung, breast, ovaries, pancreas, esophagus,
bladder and haematological tumors . However, in spite of
the posive results observed with the use of monoclonal
anbodies against PD-L1/PD-1, recent studies have revealed
an aggressive growth of tumors in a small poron of paents
[64,65]. This process of tumor progression aer
immunotherapy has been described as being associated with
amplicaon of MDM2/MDM4 genes . The MDM2/MDM4
genes inhibit the p53 tumor suppressor gene . Normally
p53 is acvated in response to DNA damage, or oncogene
acvaon, which in turn starts mechanisms of apoptosis, cell-
cycle arrest or modulaon of autophagy.
Monoclonal anbodies against PD-1 can induce the increase
synthesis of interferon gamma (IFN-γ) by T lymphocytes ,
which in turn acvates JAK-STAT signaling  resulng in
increase of interferon regulatory fator-8 (IRF8) expression .
Finally, the IRF8 binds to the MDM2 promoter inducing MDM2
higher expression  shown in Figure 1A.
Journal of Cancer Epidemiology and Prevention
© Copyright iMedPub 3
Figure 1 A. Monoclonal anbodies 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 amplicaon 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
producon of IFN-γ, expression of IRF8 and MDM2
amplicaon. In turn, not occurring suppression of p53, or
tumor growth and progression. APC=Angen presenng
cell; MHC=Major histocompability complex;
mAB=Monoclonal anbody. B. Increase in the expression of
Because the elevaon of intracellular cAMP creates an
oxidave environment that oxidizes and inacvates p56(lck) in
lymphocytes by an H2O2 dependent, PKA-independent
mechanism, and inhibits the producon of IFN-γ by nitric
oxide, PKA-dependent mechanism , the use of
phosphodiesterase inhibitors can promote the increase levels
of cAMP , hindering the producon of IFN-γ, which would
make dicult to increase the expression of IRF8, and increase
in the expression of MDM2 shown in Figure 1B.
Thus, the combinaon of a phosphodiesterase inhibitor with
an-PD-1 monoclonal anbodies 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 . Thus, the
use of TRAM-34 may be associated with hepac intra-arterial
chemotherapy, allowing a minor concentraon of the
chemotherapeuc oxuridine  in the liver with a lower
systemic toxic eect to the treatment of hepac
adenocarcinoma, primary or metastac. Because the
relevance of Orai1 and TRP channels in tumor
neovascularizaon , blockers of these channels can
diminish the adverses eects of treatment with ramucirumab,
a monoclonal anbodies against vascular endotelial growth
factor receptor 2 (VEGFR2), with an-angiogenic eect used to
the treatment of advanced gastric, gastro-oesophageal
juncon adenocarcinoma and non-small cell lung cancer
(NSCLC), with the possibility of decreased toxicity, and
adverses eects like neutropenia, febrile neutropenia and
Thus, the use of modiers of cAMP producon 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 eects of
chemotherapy, or immunotherapy.
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