A Novel Alternative for Cancer Therapy: Pharmacological Modulation of Ca2+/cAMP Intracellular Signaling Interaction

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American Journal of Pharmacology and Pharmacotherapeutics www.imedpub.com
American Journal of Pharmacology
and Pharmacotherapeutics
Research Article
A Novel Alternative for Cancer Therapy:
Pharmacological Modulation of Ca2+/cAMP
Intracellular Signaling Interaction
Afonso Caricati-Neto, Paolo Ruggero Errante, Leandro Bueno* and Bergantin
Department of Pharmacology, Laboratory of Autonomic and Cardiovascular Pharmacology, Escola
Paulista de Medicina, Universidade Federal de São Paulo, Brazil
*Corresponding author e-mail: leanbio39@yahoo.com.br
A B S T R A C T
Cancer is a major public health problem and the second leading cause of mortality around the
world. Cancer therapy has been growing in an unprecedented fashion in the past two decades.
Specific gene mutation, protein dysfunction, dysregulation of intracellular signaling pathways,
and immune response had been targeted. It has been shown that the dysregulation of intracellular
signaling pathways mediated by Ca2+ and cAMP participates in the cancer initiation, tumor
formation, tumor progression, metastasis, invasion and angiogenesis. Thereby, proteins involved
in these pathways, such as Ca2+ channels and cAMP-dependent protein kinase (PKA), represent
potential drugs targets for cancer therapy. We recently discovered that the interaction between
intracellular signaling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP signaling interaction)
participates in the regulation of several cellular responses, including neurotransmitter/hormone
secretion and neuroprotection. Due to importance of the Ca2+/cAMP signaling in the regulation
of cellular proliferation, we have proposed that the pharmacological modulation of these
signaling pathways could be a new strategy for cancer therapy.
Keywords: Ca2+/cAMP signalling interaction; Carcinogenesis; Cancer therapy.
INTRODUCTION
Cancer is a major public health problem and
the second leading cause of mortality around
the world. Cancer therapeutics has been
growing in an unprecedented fashion and
has evolved rapidly in the past two decades.
Specific gene mutation, protein dysfunction

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and dysregulation, intracellular signaling
pathways, and immune modulation have
been targeted. These therapeutic advances
came largely because of improved
understanding of the pathobiology of cancer
at the genetic and molecular levels.
Accumulating data suggest that multi-
targeted drugs may produce greater benefits
than those observed with single-targeted
therapies, which may have acceptable
tolerability profiles, and may be active
against a broader range of tumour types.
Thus, regulation of intracellular signaling
pathways is properly regarded as a
composite of multiple component pathways
involved in diverse aspects of tumour cell
function.
Several cell functions are finely regulated by
calcium ions (Ca2+) and 3',5'-cyclic
adenosine monophosphate (cAMP)1-3. Then,
dysregulation of intracellular signaling
pathways mediated by these universal
regulators of cell function had been
implicated in cancer initiation, tumor
formation, tumor progression, metastasis,
invasion and angiogenesis1-3. Some studies
showed that drugs able to interfere with the
intracellular Ca2+ signaling such as selective
Ca2+ channel blockers (CCB), as
amlodipine, inhibit proliferative response in
different cancer cells4-6. In addition, drugs
able to increase the intracellular cAMP
levels (cAMP-enhancer compounds), such
as phosphodiesterase (PDE) 4 inhibitors,
have been proposed as potential adjuvant,
chemotherapeutic or chemopreventive
agents in some cancer types, including
hepatocellular carcinoma7. Then, the
pharmacological modulation of the
intracellular signaling mediated by Ca2+ and
cAMP in the cancer cells may represent a
new therapeutic strategy for cancer
progression.
Recently, we discovered that the functional
interaction between intracellular signaling
pathways mediated by Ca2+ and cAMP
(Ca2+/cAMP signaling interaction) plays an
important role in the regulation of the
several cellular responses, including
neurotransmitter/hormone release and
neuroprotection8-14. It is well established that
the free Ca2+ in the cytosol regulates
adenylate cyclase (AC) activity and
consequently cAMP production9-13. The AC
activity is reduced in response to increase of
cytosolic Ca2+ concentration ([Ca2+]c),
decreasing the cytosolic cAMP
concentration ([cAMP]c)9-13. In contrast, the
AC activity is increased in response to the
reduction of Ca2+c, elevating [cAMP]c due
to degradation of ATP9-13.
We showed that Ca2+/cAMP signaling
interaction can be pharmacologically
modulated by combination of drugs that
reduce [Ca2+]c, such as Ca2+ channel
blockers (CCB), such as nifedepine and
verapamil, with drugs that increase [cAMP]c
(cAMP-enhancer compounds), such as
Forskolin (AC activator) and Rolipram
(phosphodiesterase (PDE) inhibitor)9-13. In
response to the reduction of Ca2+ influx
through L-type voltage-activated Ca2+
channels (VACC) produced by CCB, the
AC activity and [cAMP]c are increased9-13.
These CCB-effects can be potentiated by

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cAMP-enhancer compounds9-13. Figure 1
shows how the Ca2+/cAMP signaling
interaction can be pharmacologically
modulated by combined use of the CCB and
cAMP-enhancer compounds.
This important discovery on the cellular role
of Ca2+/cAMP signaling interaction, and its
pharmacological modulation, emerged from
numerous clinical studies performed since
1975 that reported that the use of L-type
CCB during antihypertensive therapy
decreased arterial pressure, but produced
several adverse effects including
sympathetic hyperactivity15. Despite these
CCB-effects have been attributed to adjust
reflex of arterial pressure by autonomic
system, the molecular mechanisms involved
in these effects remained unclear for
decades.
To exclude the influence of adjusting reflex,
the CCB effects on the autonomic system
was studied in isolated tissues richly
innervated by sympathetic nerves (rodent
vas deferens)8,16-18. Studies performed since
1975 showed that responses mediated by
sympathetic nerves were completely
inhibited by L-type CCB in high
concentrations (>1 μmol/L), but
unexpectedly and paradoxically potentiated
in concentrations below 1 μmol/L8,16-18. This
paradoxical CCB-induced sympathetic
hyperactivity remained unclear for decades,
but in 2013, we discovered that this effect
was caused by the increase of secretory
response from sympathetic neurons, and
adrenal chromaffin cells, stimulated by CCB
due to its modulatory action on the
Ca2+/cAMP signaling interaction in these
cells8. In addition, we discovered that the
CCB-induced sympathetic hyperactivity was
potentiated by cAMP-enhancer compounds,
such as AC activators (Forskolin and IBMX)
and PDE inhibitors (Rolipram)9-13. Our
finding showed for the first time that the
Ca2+/cAMP signaling interaction
participates in the regulation of the
transmitter/hormone from neurones and
neuroendocrine cells9-13.
Our studies also showed that the cellular
damage and death caused by cytosolic Ca2+
overload can be prevented by
pharmacological modulation of the
Ca2+/cAMP signaling interaction, due
probably to stimulation of cellular survival
pathways mediated by cAMP-response
element binding protein (CREB)10-13. Thus,
the pharmacological modulation of the
Ca2+/cAMP signaling interaction can
produce elevation of [cAMP]c and
attenuation of cytosolic Ca2+ overload,
stimulating cellular responses involved in
the neuroprotection and cardioprotection9-14.
We have proposed that the combined use of
the L-type CCB and cAMP-enhancer
compounds to pharmacologically modulate
the Ca2+/cAMP signaling interaction could
be used as a new therapeutic strategy for
neurological and psychiatric disorders
related to neurotransmission deficit, and
neuronal death, such as Alzheimer's and
Parkinson’s diseases9-13. In addition, this
pharmacological modulation could attenuate
cardiac arrhythmias and myocardial lesions
caused by ischemia and reperfision in
patients with acute myocardial infarction 14.

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Cancer therapy has been growing in an
unprecedented fashion in the past two
decades. Specific gene mutation, protein
dysfunction, dysregulation of intracellular
signaling pathways, and immune response
had been targeted1-3. It has been shown that
the dysregulation of intracellular signaling
pathways mediated by Ca2+ and cAMP
participates in the cancer initiation, tumor
formation, tumor progression, metastasis,
invasion and angiogenesis1-3. Thereby,
proteins involved in these pathways, such as
Ca2+ channels and cAMP-dependent protein
kinase (PKA), represent potential drugs
targets for cancer therapy. Due to the
important role of the dysregulation of
intracellular signaling pathways mediated by
Ca2+ and cAMP in the carcinogenesis, we
have proposed that the pharmacological
modulation of the Ca2+/cAMP signaling
interaction in cancer cells could be a new
therapeutic strategy for cancer progression
19. In this review, we will discuss how the
pharmacological modulation of the
Ca2+/cAMP signaling interaction could be a
novel alternative for cancer therapy.
Role of the intracellular Ca2+ signaling in
cancer cells
Since the beginning of life, Ca2+ ions play a
vital role for living organisms. Ca2+
mediates the fertilization process and
regulates the cell cycle events during the
early developmental processes19,20. After the
cells differentiate to perform specific
functions, Ca2+ regulates numerous cellular
processes, including energy transduction,
secretion, neuronal synaptic plasticity,
muscle contraction, cell migration,
chemotaxis cell proliferation, gene
transcription, apoptosis and others20.
Intracellular Ca2+ concentration in resting
cell is usually maintained very low at about
100 nM, due to the toxicity related to excess
of Ca2+ in cytosol20. Thus, transient
increases in [Ca2+]c activates several
intracellular signaling mediated by Ca2+,
while numerous mechanisms involved in
cellular Ca2+ homeostasis act to restore the
intracellular Ca2+ levels corresponding to the
resting state of the cell20.
In the excitable cells, the Ca2+ enters into
cell through plasma membrane voltage-
activated Ca2+ channels (VACC, also named
CaV) and transient receptor potential
channels (TRP), and triggering numerous
cells responses20. Inside the cell, Ca2+ is
stored in specific organelles, such as
endoplasmic reticulum (ER) and
mitochondria20. Several Ca2+ channels and
transporters finely regulate intracellular Ca2+
concentration, including VACC, ER Ca2+
channels regulated by inositol-1,4,5-
triphosphate (IP3R) and ryanodine (RyR)
receptors, plasmalemal (PMCA) or ER
(SERCA) Ca2+-ATPase, Na+/Ca2+
exchanger (NCX) and mitochondrial Ca2+
uniporter (MCU)20.
To utilize Ca2+ as a intracelular messenger,
cells have devised an ingenious mechanism
of signaling that has overcome the inherent
problems associated with lower diffusion
rates and cytotoxicity of Ca2+, by presenting
oscilations in Ca2+ concentration as brief

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spikes which are often organized as
regenerative waves20. In order to provide for
a very fast and effective Ca2+ signaling, the
cells spend a great amount of energy to
maintain almost 20,000-fold Ca2+ gradient
between their intra and extracellular
concentrations20. Then, the cells chelate,
compartmentalize, or remove Ca2+ from the
cytoplasm to maintain this Ca2+ gradient20.
Intracellular Ca2+ signaling in normal cells is
needed for cell proliferation, whereas tumor
cell lines show changed dependency on Ca2+
to maintain cell proliferation21,22.
Carcinogenesis is a biological process of
non-lethal genetic injury that can be
inherited in the germ line or can be acquired
by the action of environmental agents22.
This process implies in changes in proto-
oncogenes, genes proapoptotic genes, and
DNA repair genes22. Several antineoplasic
chemotherapeutic agents act in cell division,
affecting both normal and neoplastic cells. It
is well established that carcinogenesis
process is related with an increased
expression, and abnormal activation, of
proteins that participate in the intracellular
Ca2+ homeostasis, such as Ca2+ channels,
transporters and pumps23. Then, these
structures can be important therapeutic
targets for inhibiting cancer growth.
Both the genetic and epigenetic mechanisms
have been proposed for the specific roles of
intracellular Ca2+signaling in
carcinogenesis24. Due to mutations, the
normal cells can be transformed to cancer
cells by acquiring cancer-specific properties,
including uncontrollable proliferation,
immortality, and self-sufficiency in growth
signals24-26. It was showed that the
intracellular Ca2+ waves in concert with
other signal-transduction cascades regulate
several cellular processes, such as gene
expression27-29. The activation by
intracellular Ca2+ of the protein kinase, such
as PKC, causes the phosphorylation of
methyltransferases involved in DNA
methylation30.
Numerous evidences indicated that an
increased expression and function of
proteins (Ca2+ channels, transporters ,
pumps) participate in the dysregulation of
intracellular Ca2+ signaling, contributing to
cancer initiation, tumor formation, tumor
progression, metastasis, invasion and
angiogenesis1-3. For example, the
overexpression of IP3R Ca2+ release
channels that regulate Ca2+ leakage from the
ER, or reduced sequestration of Ca2+ due to
lower levels of SERCA2, could decrease
apoptotic rates1. The nucleoplasmic
reticulum releases Ca2+ independently of
signals produced by cytosolic Ca2+,
microdomain31 where Ca2+ binds to specific
DNA promoter regions, regulating the
activity of transcription factors, gene
expression and cellular activity32. Then,
these molecules involved in the intracellular
Ca2+ signalling have been proposed as
therapeutic targets for inhibiting cancer
progression23.
In cancer cells, the intracellular Ca2+
signaling pathways are remodeled, or
deregulated, changing their physiology, and
distinguish them from non-malignant
cells24,33. This remodeling, or dysregulation,

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provides means by which cancer cells can
overcome systemic anticancer defense
mechanisms. In addition, this remodeling or
dysregulation can lead to genetic diversity
found in cancerous tissues thereby providing
effective cellular strategies to the selection
pressure to acquire specific traits24,33.
It was showed that the drugs that interfere
with the intracellular Ca2+ signaling, such as
CCB (amlodipine, mibefradil and NNC-55-
0396), inhibit the proliferative response in
different tumoral cells4-6. In addition, it was
showed that the L-type VACC can directly
modify the transcription of genes and their
products, e.g., the proteolytically cleaved 75
kDa C-terminal fragment of CaV1.2, a L-
type VACC named Ca2+ channel associated
transcriptional regulator (CCAT), which
translocates to the nucleus altering the
transcription of several genes, including
Myc, Bcl-associated death promoter (Bad)
and artemin34. It was showed that the
nuclear CCAT levels increase or decrease in
response to low and high intracellular Ca2+,
respectively34. These findings support that
the pharmacological modulation of the
intracellular Ca2+ signaling in the cancer
cells could be a novel alternative for cancer
therapy.
Intracellular Ca2+ signaling in normal cells is
highly regulated spatially by ER,
mitochondria and cytoskeletal elements, and
temporally by the Ca2+ oscillations, and Ca2+
wave frequencies, amplitudes, and
durations1,20. In contrast, the spatio-temporal
regulation of intracellular Ca2+ signaling in
cancer cells is significantly modulated in
terms of frequencies, amplitudes and
duration of Ca2+ signals. The specific
targeting (Ca2+ channels, transporter or
pumps) with restricted tissue distribution,
altered expression in cancer and/or a role in
the regulation of tumorigenic pathways,
could disrupt intracellular Ca2+ homeostasis
in cancer cells. Treating both normal and
cancer cells with agents that disrupt these
pathways may kill the cancer cell33. The
altered expression of the Ca2+ channel in
cancer cells can increase the Ca2+ influx,
leading to activation of cell death pathways
and/or disruption of cell-cycle progression33.
Then, the selective alterations in the activity
of the Ca2+ channel could inhibit the Ca2+-
dependent tumorigenic pathways, including
the cell proliferation33.
L-type VACC has been implicated in the
development and progression of several
tumors, and a recent meta-analysis of
microarray datasets showed VACC mRNA
gene profile of different types of cancers35.
It was showed that the L-type VACC are
significantly up-regulated in colon and
esophageal cancer [36-40]. Novel splice
variants of T-type VACC are commonly
detected in human glioma, breast, ovarian,
prostate colon and esophageal cancer cells36-
40. For example, the Cav3.1a transcripts
predominate in the normal adult brain, but
human glioma and glioma cell lines contain
Cav3.1bc as predominant splice and
Cav3.1ac as a novel splice variant, which is
absent in normal brain36-40.
Several drugs that interfere with the
intracellular Ca2+ signaling, such as CCB,

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inhibit proliferative response in different
tumoral cells4-6,41. For example, the L-type
VACC blocker amlodipine inhibited both in
vitro and in vivo the growth of human
epidermoid carcinoma A431 cells, via
arresting cell cycle at G1 phase, and
reducing phosphorylation of retinoblastoma
protein, expression levels of cyclin D1 and
cyclin dependent kinase4. In addition, the T-
and L-type VACC blocker mibefradil
reduced tumor size, to improve the survival
rate in glioma animal model as well as in a
patient derived pancreas xenograft animal
model36,42. A novel mibefradil-derived
compound NNC-55-0396 inhibited
angiogenesis in cancer cells, becoming a
promising chemotherapy drug6,36.
It is important to mention that the cancer
therapy with drugs that interfere in the
intracellular Ca2+ signaling, such as CCB,
could be useful to control growth of cancer
with high rates of resistance to conventional
radiotherapy and chemotherapy treatments,
or in combination with immunotherapy, to
decrease dose of monoclonal antibodies
intravenously infused, and their adverse
effects32. The use of these drugs in
association with existing cancer therapy may
reduce the doses and adverse effects
generated by radiotherapy and
chemotherapy, conferring better quality of
life to patients, and increase of global
survival rate of patients with cancer.
cAMP is a derivative of adenosine
triphosphate (ATP) produced by enzymatic
action of AC. This chemical messenger is
used for intracellular signal transduction in
many different organisms, conveying the
cAMP-dependent pathway. cAMP regulates
a large variety of cell functions in response
to activated G-protein coupled receptors.
The increase of [cAMP]c activates cAMP-
dependent protein kinase (PKA), stimulating
various cellular process. The widespread
expression of PKA subunit genes, and the
myriad of mechanisms by which cAMP is
regulated within a cell suggest that
cAMP/PKA signaling is vital for cellular
function involved in the regulation of a wide
variety of cellular processes, including
metabolism, ion channel activation, cell
growth and differentiation, gene expression
and apoptosis43. Since it has been implicated
in the initiation and progression of tumors,
PKA has been proposed as a novel
biomarker for cancer detection, and as a
potential molecular target for cancer
therapy43.
cAMP exerts positive or negative effects on
cell proliferation in different cell types.
Several in vitro studies have shown that the
cAMP is a mitogenic factor in somatotrophs
and in other endocrine cells. Some
evidences suggest that the mutations of
genes coding for proteins that contribute to
increases in the cAMP signaling cascade
may cause endocrine tumor development.
Although the role of intracellular cAMP
signaling in cancer cells has been poorly
investigated, the drugs that increase the
intracellular cAMP concentration (cAMP-
enhancer compounds), such as PDE 4
inhibitor Rolipram, have been proposed as
potential adjuvant, chemotherapeutic or
chemopreventive agents in hepatocellular

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carcinoma7. It was showed that cAMP-
enhancer compounds produce cytoprotective
effect in cancer model rats44. The
impairment of cAMP and/or cGMP
generation by overexpression of PDE
isoforms has been reported in various types
of cancer45. The inhibition of selective PDE
isoforms produces increase of the
intracellular cAMP and/or cGMP levels,
inducing apoptosis and cell cycle arrest in a
broad spectrum of tumour cells45. In
addition, the inhibition of selective PDE
isoforms regulates the tumour
microenvironment45. This strategy may offer
promising insight into future cancer therapy.
We have proposed that the development and
clinical application of drugs that modulate
intracellular signaling mediated by Ca2+ and
cAMP may selectively restore normal
intracellular signalling, providing
antitumour therapy with reduced adverse
effects. Thus, our recent discovery of the
role of Ca2+/cAMP signaling interaction in
the regulation of several cellular responses9-
13opened the possibility that
pharmacological modulation of these
signalings could be useful in the cancer
therapy.
The regulation of cyclic nucleotide signaling
is properly regarded as a composite of
multiple component pathways involved in
diverse aspects of cancer cell function. This
'pathway approach' targeted to cAMP has
identified AC activators (e.g., AC7), PDE
inhibitors (e.g., PDE7B) and/or activators or
inhibitors of downstream mediators (PKA
and Epac, respectively), which might be
utilized therapeutically in chronic
lymphocytic leukemia46. Therapy directed at
such targets may prove to be clinically
useful, and may also provide a proof-of-
principle of the utility of targeting cAMP
signaling in other types of cancer46.
Intracellular cAMP signaling, through the
PKA-dependent and/or-independent
pathways, is very relevant to cancer and its
targeting has shown a number of antitumor
effects, including the induction of
mesenchymal-to-epithelial transition,
inhibition of cell growth and migration and
enhancement of sensitivity to conventional
antitumor drugs in cancer cells47. It was
showed that the AC activator forskolin
produces antitumor effects due to increase of
[cAMP)c47. The 8-Cl-cAMP, and the PKA I-
selective cAMP analogs (8-
piperidinoadenosine-3',5'-cyclic
monophosphate (8-PIP-cAMP) and 8-
hexylaminoadenosine-3',5'-cyclic
monophosphate (8-HA-cAMP) produced
antiproliferative effect in human cancer cell
lines48.
The anti-proliferative effect of the PKA I-
selective cAMP analogs was atributted to
growth arrest, while the 8-Cl-cAMP appears
produce pro-apoptotic effect. It also
observed that the PKA I-selective cAMP
analogs, but not 8-Cl-cAMP, inhibited ERK
phosphorylation, whereas 8-Cl-cAMP alone
induced a progressive phosphorylation of
the p38 mitogen-activated protein kinase
(MAPK), via activation of AMPK by its
metabolite 8-Cl-adenosine48. Pro-apoptotic
effect of 8-Cl-cAMP appears to be
prevented by pharmacological inhibition of

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the p38 MAPK. These findings suggest that
8-Cl-cAMP and the PKA I-selective cAMP
analogs could be used in human cancer
therapy.
Interestingly, the 8-Cl-cAMP and PKA type
I-selective cAMP analogs (8-PIP-cAMP and
8-HA-cAMP) also showed a potent
antiproliferative effect in medullary thyroid
cancer cell lines49. It was showed that the 8-
Cl-cAMP significantly inhibited the
transition of cell population from G2/M to
G0/G1 phase and from G0/G1 to S phase49.
In addition, the 8-Cl-cAMP induced
apoptosis in medullary thyroid cancer cell
lines49. This finding demonstrated that
cAMP analogs, particularly 8-Cl-cAMP,
significantly suppress cell proliferation in
medullary thyroid cancer cell lines and
provide rationale for a potential clinical use
of drugs that interfere with cAMP/PKA
signalling in the cancer therapy.
Pharmacological modulation of Ca2+/cAMP
signalling interaction in cancer cells as a
new therapeutic strategy of cancer. It is
interesting to note that since the 1980s there
was an increase in research identifying
genetic and molecular targets, and in clinical
trials, using biomarkers able to detect the
presence of genetic or molecular markers in
a patient's cancer to select appropriate
targeted therapy. This advance in the
diagnosis and therapy of cancer has been
made possible by increased knowledge of
the genetic pathogenesis of cancer, and by
increased capacity to sequence genes and
genomes in clinically useful timeframes.
But, many challenges and pitfalls remain in
selecting optimal targets, designing effective
targeted drugs and antibodies, and
identifying appropriate combinations of
therapies are required. Therefore, the current
knowledge about regulation of intracellular
Ca2+ and cAMP signalling in cancer cells,
and the search for new pharmacological
strategies to control these intracellular
messengers may contribute to the
development of new pharmacological
strategies that specifically alter tumor
growth, angiogenesis and metastasis,
without affecting normal cell physiology.
The control of the intracellular Ca2+
signaling has been described as an important
strategy to reduce the rate of cancer tumor
proliferation31,32,50-52. In addition, the
intracellular cAMP signaling is very
relevant to cancer, and its targeting has
shown a number of antitumor effects and the
enhancement of sensitivity to conventional
antitumor drug therapy47. In fact, several
drugs that interfere with the intracellular
signalings mediated by Ca2+ and cAMP
inhibit tumor growth, angiogenesis and
metastasis in different tumoral cells4-7,36,42-50.
Then, the pharmacological modulation of
the Ca2+/cAMP signaling interaction in the
tumoral cells may represent a new
therapeutic strategy of cancer progression19.
In combination with existing antitumor
therapies, the pharmacological modulation
of the Ca2+/cAMP signaling interaction may
be able to reduce the doses and adverse
effects generated by radiotherapy and
chemotherapy, conferring better quality of
life to patients, and increase of global
survival rate of patients with cancer. This

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combined therapy could be used to control
growth of cancer tumors with high rates of
resistance to conventional radiotherapy, and
chemotherapy treatments51,52. In addition,
the pharmacological modulation of the
Ca2+/cAMP signaling interaction could be
used in combination with immunotherapy to
decrease dose of monoclonal antibodies
intravenously infused, and their adverse
effects53. It also important to mention that
the CCB and cAMP-enhancer compounds
used to modulate the Ca2+/cAMP signaling
interaction are actually used in
antihypertensive, and antidepressant,
therapy with good tolerability by most
patients.
We have proposed that the pharmacological
modulation of the Ca2+/cAMP signalling
interaction could be a more efficient
therapeutic approach to reduce cancer tumor
growth, angiogenesis and metastasis,
without affecting normal cell physiology
deserves special attention. It would not be a
surprise the suggestion of using CCBs in
combination with pharmaceuticals which
increase cAMP to inhibit cancer
progression8-13. Then, the pharmacological
modulation of the Ca2+/cAMP signalling
interaction could be an efficient therapeutic
strategy to prevent cancer progression.
CONCLUSION
Considering that the dysregulation of
intracellular signaling pathways mediated by
Ca2+ and cAMP participates in the cancer
initiation, tumor formation, tumor
progression, metastasis, invasion and
angiogenesis, and proteins involved in these
signaling represent potential drugs targets
for cancer therapy, we have proposed that
the pharmacological modulation of the
Ca2+/cAMP signalling interaction could be
an alternative strategy more efficient and
safer for cancer therapy.
DISCLOSURE STATEMENT
Caricati-Neto and Bergantin thank the
continued financial support from CAPES,
CNPq and FAPESP (Bergantin´s
Postdoctoral Fellowship FAPESP
#2014/10274-3).
The authors also thank Elsevier - “author
use”: Reuse of portions or extracts from the
article in other works.
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Figure 1. Pharmacological modulation of the Ca2+/cAMP signaling interaction