The Pharmacological Interference on the Ca 2+ /cAMP Intracellular Signalling Pathways: Advances for the Antitumoral Immunotherapy Research

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2017
Vol. 1 No. 1:4
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© Under License of Creative Commons Attribution 3.0 License | This article is available in: http://www.imedpub.com/immunotherapy-research-journal/
Immunotherapy Research Journal
Editorial
Paolo Ruggero Errante,
Francisco Sandro Menezes-
Rodrigues,
Afonso Caricati-Neto and
Leandro Bueno Bergantin*
Department of Pharmacology, Laboratory of
Autonomic and Cardiovascular, Universidade
Federal de São Paulo, Escola Paulista de
Medicina, São Paulo, Brazil
*Corresponding author:
Leandro Bueno Bergann
 leanbio39@yahoo.com.br
Department of Pharmacology, Laboratory
of Autonomic and Cardiovascular
Pharmacology, Universidade Federal de
São Paulo, Escola Paulista de Medicina, São
Paulo, Brazil.
Tel: 55 11 5576-4973
Citaon: Errante PR, Menezes-Rodrigues FS,
Carica-Neto A, Bergann LB (2017)
The Pharmacological Interference on
the Ca2+/cAMP Intracellular Signalling
Pathways: Advances for the Antumoral
Immunotherapy Research. Immunother Res.
Vol. 1 No. 1:4
The Pharmacological Interference on
the Ca2+/cAMP Intracellular Signalling
Pathways: Advances for the Antumoral
Immunotherapy Research
Received: August 11, 2017; Accepted: August 12, 2017; Published: August 21, 2017
Cancer is considered a worldwide public health problem,
with a large annual number of deaths, and treatment public
spending [1]. Convenonal treatments such as chemotherapy
and radiotherapy have limitaons since they are not selecve
and specic, aecng both: tumor and healthy cells [2]. In
recent years, new therapies have been emerged, such as: target
therapies and immunotherapy both used as monotherapy or in
combinaon with convenonal therapies [3-5].
Immunotherapy for the treatment of cancer, using monoclonal
anbodies, is considered selecve, such as anbodies against
Vascular Endothelial Growth Factor (VEGF) [6]. This therapeuc
approach has signicant ecacy in the treatment of dierent
types of tumors, but its cost and toxic eects limit its applicaon
[7]. Thus, one of the greatest challenges is the development
of combined therapies capable of inducing an antumor
response, availing the control of tumor growth, angiogenesis and
disseminaon [8].
In the early stages of tumor development, when the tumor is
less than 2 mm of diameter, the nutrion of the tumor mass
is performed through the diusion from neighboring ssues.
Exceeding this size, tumor growth depends on the process of
angiogenesis and the new formed blood vessels serve as routes for
disseminaon of the neoplasia to other places (colonizaon) [9].
For tumor-induced angiogenesis occurring, αvβ3 integrins play
a relevant role in the physical interacon with the extracellular
matrix necessary for cell adhesion, migraon and posioning,
in addion to inducing signs for cell survival and proliferaon
[10]. Integrins are adapted for the transmission of informaon
from the extracellular medium into the cells by cytoskeleton
proteins, with acvaon of GTPases, acvaon of Mitogen
Acvated Protein-Kinase (MAPK), alteraon of intracellular
levels of Ca2+ and increase of levels of substrates for acvaon
of phospholipase C [11,12]. Acvaon of phospholipase C causes
increased hydrolysis of membrane phospholipids, generang
inositol-1-4-5-triphosphate and diacylglycerol. Inositol-1-4-5-
triphosphate acvates Ca2+ channels located in the membrane
of the endoplasmic reculum, releasing Ca2+ into the cytosol;
and thus diacylglycerol acvates the plasma membrane voltage
sensive Ca2+ channels, with passage of Ca2+ from extracellular
into intracellular compartment [13]. Thus, this signaling system
- with increased levels of intracellular Ca2+ - may contribute to
the process of tumor growth and disseminaon, exemplied by
sarcoplasmic/endoplasmic reculum calcium ATPases channels
(SERCA, specically SERCA2, SERCA3) and voltage-gated Ca2+
channels (CaV, specically CaV1.2, CaV3.2) [14-16].
In addion, the blockade of Ca2+ channels is able to decrease
vascularizaon in breast and kidney tumors; and the drug NNC
55-0396, a T-type Ca2+ channel inhibitor, is capable of inhibing
angiogenesis of tumor by suppression of hypoxia-inducible factor-
1alpha signal transducon via both proteasome degradaon, and
protein synthesis pathways [17,18].
Besides Ca2+ the cyclic adenosine monophosphate (cAMP) is a
nucleode responsible for intracellular signalling transducon
from dierent smuli, associated with acvaon of protein

2
2017
Vol. 1 No. 1:4
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Immunotherapy Research Journal
kinases [19,20]. The decrease of intracellular levels of cAMP
smuli may modulate transcriponal factors, and gene acvaon,
making cells start DNA synthesis, and entry to cell cycle [21]. In
contrast, increasing intracellular levels of cAMP through the
acon of phosphodiesterase inhibitors (that hydrolyze cAMP)
may inhibit Endothelial Extracellular Matrix (ECM) remodeling,
thus suppressing PI3K/AKT signals to down-modulate Vascular
Endothelial Growth Factor (VEGF) secreon and vessel formaon
in vitro, and smuling the lower synthesis of VEGF and diminishing
the micro vessel density in animal model of diuse large B-cell
lymphoma (DLBCL) [22,23]. Also, the associaon of curcumin
with phosphodiesterase 2, and phosphodiesterase 4 inhibitors,
inhibits the producon of VEGF, angiogenesis and tumor growth
[24]. Thus, the combinaon of an-VEGF monoclonal anbodies
with Ca2+ channel blockers or phosphodiesterase inhibitors, may
decrease the toxic eects of antumor immunotherapy.
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