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:
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.
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.
Cancer progression; Ca2+ channels blockers; Second messenger; Cyclic adenosine monophosphate, Ca2+/
Cancer is an important cause of morbidity and mortality worldwide,
leading to the rise of great economic costs in the diagnosis and
treatment . Despite the great scientic advances regarding the
tracking of tumor cells by liquid biopsy , interventions on tumors
are still limited to surgery, chemotherapy, radiotherapy and
immunotherapy . Many patients discontinue the treatment because
of the great number of toxic and adverse eects 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 . 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 eects and the
abandonment rate in dierent 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 dierent channels and transporters, such as the receptor
of inositol-1,4,5-triphosphate (IP3R) and Ca2+-ATPase pump . 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 .
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
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 , 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 .
Numerous transporters of Ca2+, like members of Ca2+-ATPases
family such as SERCA, present altered expression of isoforms in
dierents tumors cells . A change in the expression of TRP
channels , L-type calcium channel , and T-type Ca2+ channels
 were observed in tumors cells .
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  or NecroX-5  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, dierentiation and cellular growth .
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 dierent types of tumors , and the pharmacological
manipulation of cAMP may lead to the decrease of tumor progression
Advances in Cancer Prevention Errante et al., Adv Cancer Prev 2017, 2:2
Editorial OMICS International
Adv Cancer Prev, an open access journal
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 dierent
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 eects 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
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Adv Cancer Prev, an open access journal
Volume 2 • Issue 2 • 1000e105