Targeting Calcium Signaling in Cancer Therapy

Acta Pharmaceutica Sinica B 2017;7(1):3–17
Chinese Pharmaceutical Association

Institute of Materia Medica, Chinese Academy of Medical Sciences
Acta Pharmaceutica Sinica B
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REVIEW
Targeting calcium signaling in cancer therapy

Chaochu Cuia,b, Robert Merrittb,c, Liwu Fua, Zui Panb,c,d,n
a
State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine,
Sun Yat-sen University Cancer Center, Guangzhou 510060, China
b
Department of Surgery, Division of Thoracic Surgery, The Ohio State University, Columbus, OH 43210, USA
c
Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
d
College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76019, USA
Received 21 October 2016; accepted 28 October 2016
KEY WORDS Abstract The intracellular calcium ions (Ca2þ) act as second messenger to regulate gene transcription,
Ca2þ channels; cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca2þ
Store-operated Ca2þ entry; homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis,
Cell proliferation; progression and metastasis. Targeting derailed Ca2þ signaling for cancer therapy has become an emerging
Migration; research area. This review summarizes some important Ca2þ channels, transporters and Ca2þ-ATPases,
Apoptosis; which have been reported to be altered in human cancer patients. It discusses the current research effort
Channel blockers;; toward evaluation of the blockers, inhibitors or regulators for Ca2þ channels/transporters or Ca2þ-ATPase
Cancer therapy pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for research
Abbreviations: 20-GPPD, 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol; CaM, calmodulin; CaMKII, calmodulin-dependent protein kinase II; CBD,
cannabidiol; CBG, cannabigerol; CPZ, capsazepine; CRAC, Ca2þ release-activated Ca2þ channel; CTL, cytotoxic T cells; CYP3A4, cytochrome P450 3A4;
ER/SR, endoplasmic/sarcoplasmic reticulum; HCX, Hþ/Ca2þ exchangers; IP3, inositol 1,4,5-trisphosphate; IP3R (1, 2, 3), IP3 receptor (type 1, type 2, type
3); mAb, monoclonal antibody; MCU, mitochondrial Ca2þ uniporter; MCUR1, MCU uniporter regulator 1; MICU (1, 2, 3), mitochondrial calcium uptake
(type 1, type 2, type 3); MLCK, myosin light-chain kinase; NCX, Naþ/Ca2þ exchanger; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor-
κB; NSCLC, non-small cell lung cancer; OSCC, oral squamous cell carcinoma cells; PKC, protein kinase C; PM, plasma membrane; PMCA, plasma
membrane Ca2þ-ATPase; PTP, permeability transition pore; ROS, reactive oxygen species; RyR, ryanodine receptor; SERCA, SR/ER Ca2þ-ATPase; SOCE,
store-operated Ca2þ entry; SPCA, secretory pathway Ca2þ-ATPase; TEA, tetraethylammonium; TG, thapsigargin; TPC2, two-pore channel 2; TRIM, 1-(2-
(trifluoromethyl) phenyl) imidazole; TRP (A, C, M, ML, N, P, V), transient receptor potential (ankyrin, canonical, melastatin, mucolipin, no
mechanoreceptor potential C, polycystic, vanilloid); VGCC, voltage-gated Ca2þ channel
n
Corresponding author at: College of Nursing and Health Innovation, The University of Texas at Arlington, LS Building 239, 501 S. Nedderman Dr.,
Arlington, TX 76019, USA. Tel.: +1 817 272 2261.
E-mail address: [email protected] (Zui Pan).
Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.
http://dx.doi.org/10.1016/j.apsb.2016.11.001
2211-3835 & 2017 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by
Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
4 Chaochu Cui et al.
into the understanding of cellular mechanisms underlying the regulation of Ca2þ signaling in different
cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca2þ channels or
transporters.
& 2017 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical
Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction research area toward evaluation of a certain numbers of Ca2þ

channel blockers or regulators and Ca2þ-ATPase pump inhibitors
Intracellular calcium ions (Ca2þ), the most abundant second messen- as anti-cancer drugs.
ger in human body, have a substantial diversity of roles in
fundamental cellular physiology, including gene expression, cell
cycle control, cell motility, autophagy and apoptosis1. Since the
2. Altered Ca2þ channels/transporters in cancer
cytosol Ca2þ is maintained very low (10 7 mol/L), a small
fraction of Ca2þ either through release from intracellular organelles
The intracellular Ca2þ homeostasis is governed by a network
( 10 5 mol/L) or through influx from extracellular reservoir
composed of various Ca2þ channels and transporters: (1) IP3R or
( 10 3 mol/L) can generate marked signals to activate downstream
ryanodine receptor (RyR) mediating Ca2þ release from endoplasmic/
signaling cascade. Increase in Ca2þ levels are highly localized, such
sarcoplasmic reticulum (ER/SR); (2) Ca2þ-ATPase pumping Ca2þ
as the microdomains in the vicinity of inositol 1,4,5-trisphosphate
from cytosol back to ER/SR or extracellular space; (3) Ca2þ channels
receptor (IP3R) or store-operated Ca2þ entry (SOCE) channel2.
or transporters allowing Ca2þ influx across plasma membrane (PM)
Alternatively, local changes in intracellular Ca2þ can diffuse across
from extracellular Ca2þ reservoir, such as voltage-gated Ca2þ channel
the cell as a wave and elicit an effect at a distant site3. The prolonged
(VGCC), transient receptor potential channel (TRP), Ca2þ release-
intracellular elevation of Ca2þ can be toxic and triggers cell death4.
activated Ca2þ channel (CRAC), Naþ/Ca2þ exchanger (NCX) and
Therefore, the Ca2þ signals in the form of waves, spikes or
purinergic receptor; (4) mitochondrial Ca2þ uniporter (MCU) regulat-
oscillations must be spatially-temporally tightly regulated5.
ing mitochondrial Ca2þ uptakes (Fig. 1). It is beyond the scope of this
Among the three Ca2þ signal forms, intracellular Ca2þ oscilla-
brief review to cover all the Ca2þ channels, transporters or Ca2þ-
tions provide efficient means to transmit intracellular biological
ATPases for intracellular Ca2þ homeostasis; instead, we will focus on a
information. For example, our previous study showed that
few important ones, which have been reported to be dysregulated in
intracellular Ca2þ oscillations provided essential proliferation
cancer cells (Table 1).
signals for esophageal cancer cells6. In particular, the frequency,
amplitude, and duration of these intracellular Ca2þ oscillations
compose the specific Ca2þ codes for selective activation of
transcription factors for gene transcription, cell proliferation and
migration7,8. The decoding of the oscillatory form is achieved by
intracellular downstream effectors, including calmodulin (CaM),
nuclear factor of activated T-cells (NFAT), nuclear factor-κB (NF-κB),
calmodulin-dependent protein kinase II (CaMKII) and calpain,
which differ in their on- and off-rates for Ca2þ and subsequently
activate different cellular processes9–11. Furthermore, different
Ca2þ regulated kinases and enzymes often occupy distinct loca-
tions within the cell. Therefore, the size, kinetics and spatial profile
of a cytoplasmic Ca2þ signal are all important in determining
which Ca2þ-dependent response will be activated, when and for
how long. Intracellular Ca2þ oscillations can reduce the effective
Ca2þ threshold for signaling transduction, thereby increasing
signal detection at low levels of stimulation12.
Disruption of normal Ca2þ signaling contributes to the devel-
opment of malignant phenotypes13. In order to proliferate at high Figure 1 Important Ca2þ channels/transporters/pumps in cancer
rates, to increase cell motility and invasion, to escape death, to fool cells. The dynamic of intracellular Ca2þ is governed by a series of
immune-attack, or to have neovascularization, tumors remodel proteins: (1) IP3Rs mediating Ca2þ release from endoplasmic reticu-
their Ca2þ signaling network. There has been an increasing lum (ER); (2) Ca2þ-ATPases pumping Ca2þ from cytosol to the ER or
awareness that tumorigenic pathways are associated with altered to extracellular space; (3) plasma membrane Ca2þ channels or
expression level or abnormal activation of Ca2þ channels, trans- transporters, such as VGCCs, TRPs, CRACs, NCXs and P2 receptors;
porters or Ca2þ-ATPases6,14–20. Correction of these derailed Ca2þ (4) mitochondrial Ca2þ uniporter. The tightly regulated Ca2þ signals
signals could provide potential cancer therapies. In this review, we in the form of waves, spikes or oscillations can regulate a wide range
will summarize the Ca2þ channels, transporters and Ca2þ- of cellular events, including gene transcription, proliferation, migration
ATPases, which are altered and play important roles in cancer and apoptosis. Targeting the dysregulated Ca2þ channels/transporters/
biology. We will also discuss the current effort in this emerging pumps may provide a promising chemotherapy for cancer patients.
Targeting calcium signaling in cancer therapy 5
2.1. IP3Rs — ER Ca2þ release channels 2.2. Ca2þ-ATPases
ER and SR are the major intracellular Ca2þ storage organelles in The low cytosolic Ca2þ concentration is maintained by the Ca2þ
non-excitable and excitable cells, respectively. While RyRs are transport system, i.e. Ca2þ-ATPases. They rapidly pump cytosolic
predominantly expressed in excitable cells, IP3Rs are the main Ca2þ ions back into intracellular organelles, e.g. ER, or to extrude
intracellular Ca2þ release channels in non-excitable cells, includ- Ca2þ ions to extracellular space. These Ca2þ-ATPases belong to
ing many cancer cells. So far, three isoforms of IP3R, i.e. IP3R1, the superfamily of P-type ATPase (E1E2-type) and can be further
IP3R2 and IP3R3 have been identified, which display different divided into three subtypes according to their subcellular localiza-
affinity to IP3 with similar but not identical functional properties21. tions: plasma membrane Ca2þ-ATPase (PMCA), ER/SR Ca2þ-
The general domain structure of IP3Rs includes the IP3 binding site ATPase (SERCA), golgi/golgi-derived vesicles secretory pathway
at the N-terminal region, the six transmembrane spanning domains Ca2þ-ATPase (SPCA). Each subtype contains multiple isoforms
at the C-terminal, a large number of cytoplasmic regulatory sites and splice variants, which present tissue-specific expression,
and protein-binding domains. Among these protein-binding regulation, and kinetic characteristics. As such, the Ca2þ-ATPases
domains, a significant one between amino acid 1390–1409 contribute to a highly complex and fine-tuned intracellular Ca2þ
mediates the interaction with the BH4 domain of anti-apoptotic signaling network30.
protein Bcl-2. IP3R-mediated ER Ca2þ release participates in the Among the Ca2þ-ATPases family members, SERCA is the best
overall intracellular Ca2þ signaling network and regulates funda- characterized one. SERCA is responsible for replenishing ER
mental cellular functions, such as cell proliferation and differentia- Ca2þ stores, maintaining protein proper folding/maturation
tion22. Moreover, recent studies have demonstrated that whereas dysregulated SERCA results in depleted or overloaded
mitochondria and ER can form structural link. Together with ER lumen Ca2þ stores, increased ER stress, dysregulated chaper-
other interacting proteins, such as BCL-2 and BAX/BAM, the ones and synthesis of lipids. Mutations and altered expression
Ca2þ channels residing in the two organelles are assembled in a levels of SERCA isoforms have been identified in various cancers,
macromolecular complex in which the IP3R directly stimulates the such as cancers of colon, gastric, lung, myeloid leukemia and
mitochondrial Ca2þ uptake23. Through this ER/mitochondrial choroid plexus tumors31 (Table 1). Overexpression of SERCA2
crosstalk, IP3Rs can further determine the cell fate by controlling was found in colorectal cancer cells, which may drive proliferation
the mitochondrial Ca2þelevation and metabolism. and migration32. On the other hand, SERCA3 was reported to have
Altered IP3R activity and/or the remodeling of IP3R-expression progressively lost during multistage process of colon tumorigen-
profile have been found in a number of cancers (Table 1). esis after initial increased expression during cell differentiation33.
Compared with normal brain tissues, human glioblastoma samples In B lymphocytes, SERCA3 was also found to be downregulated
present decreased IP3R1 and increased IP3R3. Kang et al.24 after the infection of Epstein Barr virus, a human gammaherpes-
demonstrated that caffeine could inhibit IP3R3-mediated Ca2þ virus involved in various malignancies including Burkitt's and
release, thus reduced migration of cultured glioblastoma cells and other lymphomas34.
greatly increased mean survival in a mouse xenograft model of Altered expression of SPCA isoforms occurs in various types of
glioblastoma. The upregulation of IP3R3 has been observed in cancer including breast, colon and prostate20. Clinical data showed
gastric cancer cell lines established from malignant ascites, but not that SPCA1 is highly expressed in basal-like breast cancers and
in a cell line established from primary tumor or normal gastric has a low expression in the luminal subtypes35. Feng et al.36
epithelial cells25. In a clinical association study, Shibao et al.26 identified up-regulation of SPCA2 in breast cancer-derived cells
examined whether gain of expression of IP3R isoforms is and human breast tumors. Knockdown of SPCA2 resulted in
associated with development of colorectal cancer using colorectal attenuated growth as well as decreased colony formation of MCF7
carcinomas tissues surgically resected from over a hundred cells in soft agar and reduced tumor formation in xenografted
patients. They found that IP3R1 and IP3R2 were expressed in mice. Furthermore, overexpression of SPCA2 is able to confer
both normal colorectal mucosa and colorectal cancer, while IP3R3 increased proliferation and colony formation capability in soft agar
was only observed in colorectal cancer, especially in the advancing assay in MCF10A cells, a nonmalignant mammary epithelial cell
margins of tumors correlated with depth of invasion, lymph node line. On the other hand, knockdown of SPCA2 and low Ca2þ
metastasis, liver metastasis, and TNM stage. High expression of conditions are able to decrease activity of ERK1/2 pathway, which
IP3R3 is associated with aggressiveness of colorectal carcinoma may result in decreased proliferation in breast cancer cells. SPCA2
since it is related with decreased 5-year survival. A mutation in appears to have the unique ability to elicit store-independent Ca2þ
IP3R3 encoding gene ITPR3 was identified in genetic landscape of entry, i.e. a constitutive Ca2þ entry pathway, which in turn
metastatic and recurrent head and neck squamous cell carci- promotes proliferative potential of cancer cells36.
noma27. Similarly like IP3R1 and IP3R3, the dysregulation of The association between altered PMCAs and cancer has been
IP3R2 was observed in chronic lymphocytic leukemia cells28. The reported in a few studies as well (Table 1). PMCA2, the isoform
expression of IP3R2 is significantly upregulated, which in turn predominantly expressed in mammary epithelia for the apical
may enhance mitochondrial function and energy production to efflux of Ca2þ during lactation, is highly expressed in certain
accommodate for the higher metabolic activity and the induced numbers of breast cancer cell lines37. In these breast cancer cell
proliferation of leukemia cells. It is notable that the role of IP3R2 lines, PMCA2 is constitutively expressed at levels as over 100-fold
may be complicated. Ouyang et al., recently reported that IP3R2 high as in non-tumorigenic lines. As such, PMCA2 can keep low
mediated Ca2þ signaling is required to reinforce the developmen- cytosolic Ca2þ levels and bypass apoptosis by preventing
tally important transcription factor TCF-1 for normal development increased uptake of Ca2þ into mitochondria. On the contrary,
and thymocyte neoplasia prevention. Mice without IP3Rs in PMCA4 and PMCA1 are down-regulated in colon or oral
thymocyte developed aggressive T-cell malignancies that resemble squamous cell carcinoma, respectively, which increase cytosolic
human T-cell acute lymphoblastic leukemia29. Ca2þ to enhance cell proliferation38,39. These observations suggest
that different cancer cells may develop different means to fulfill expression of TRP channels has been proposed as a tool for
special needs for intracellular Ca2þ signaling, and either up or diagnosis or predicting prognosis in several cancers, and targeting
down regulation of Ca2þ-ATPases is used to facilitate a particular TRP channels has been suggested as a novel therapeutic strategy48.
type of cancer cells to escape from normal cellular control and to
promote tumorigenesis.
2.3.3. Orai and STIM
Another type of Ca2þ influx channels, including CRAC,
2.3. Plasma membrane Ca2þ channels arachidonate-regulated Ca2þ entry channel and SOCE channel
has been demonstrated to heavily involve in cancer biology
2.3.1. Voltage-gated Ca2þ channels (Table 1). The activation of canonic SOCE pathway contains
VGCCs (also known as Cav family) mediate a fast Ca2þ influx in several steps, i.e. reduction or depletion of ER Ca2þ stores,
response to membrane depolarization. There are 6 subfamilies of translocation of ER-localized Ca2þ sensor STIM1 to ER-plasma
VGCCs, i.e. L-, N-, P-, Q-, R- and T-type. The Cav1 conducts L- membrane junctions, aggregation and conformational changes of
type Ca2þ currents, initiating muscle contraction and endocrine cell surface Orai channels, and final Ca2þ influx. To date, three
secretion; the Cav2 conducts N-, P/Q- and R-type Ca2þ currents, isoforms of Orai (Orai1, Orai2 and Orai3) and two isoforms of
initiating rapid synaptic transmission; the Cav3 conducts T-type STIM (STIM1 and STIM2) have been identified in mammals63.
Ca2þ currents, which are characterized by more rapid activation Among these SOCE machinery proteins, Orai1 and STIM1 are
and inactivation by membrane depolarization40. the two well characterized. Yang et al.64 first reported that STIM1
A recent meta-analysis of microarray datasets revealed VGCCs and Orai1 played a crucial role in breast cancer migration and
mRNA gene profile of different types of cancers41. L-type Ca2þ metastasis. We also showed that Orai1 expression was elevated in
channels are implicated in the development and progression of tumor tissues compared with normal adjacent tissues removed from
several tumors, such as significantly up-regulated in colon and patients suffering from esophageal squamous cell carcinoma; more
esophageal cancers. Novel splice variants of T-type Ca2þ channel importantly, the elevated Orai1 expression was associated with poor
are commonly found in human glioma, breast, ovarian, prostate prognosis. Inhibition of Orai1 channel either by pharmacological
colon and esophageal cancer cells. For example, Cav3.1a transcripts compounds or knocking-down of Orai1 expression could block
predominate in the normal adult brain and Cav3.1b is mostly fetal- cancer cell proliferation and migration in vitro and tumor growth
specific; but human glioma and glioma cell lines contains Cav3.1bc in vivo6. Later, Orai1 and STIM1 were also found to promote cell
as predominant splice and Cav3.1ac as a novel splice variant, which proliferation, migration, invasion and apoptotic resistance in glio-
is absent in normal brain or fetal astrocytes42–46. blastoma65, pancreatic adenocarcinoma66, prostate cancer67,68, hepa-
tocellular carcinoma69, and clear cell renal cell carcinoma70.
Interestingly, STIM1 and STIM2 are involved in the anti-tumor
2.3.2. TRP channels
activity of cytotoxic T cells, i.e. secretion of cytokines, such as
The super family of TRP channels include more than 30 members,
TNFα, IL-2 and IFNγ, which induce apoptosis of cancer cells71,72.
which can be further divided into 7 subgroups, i.e. TRPA (ankyrin),
Studies about roles of STIM2 in cancer still unconsolidated. A few
TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP
reports demonstrated STIM2, as a proliferation suppressor, con-
(polycystic), TRPN (no mechanoreceptor potential C), and TRPV
tributed to apoptotic resistance in colorectal cancer cells; while
(vanilloid)47. Mammalian TRP proteins form homo- or hetero tetra-
others revealed STIM2-mediated SOCE promote melanoma cells
meric as non-selective Ca2þ-permeable cation channels, which can be
proliferation73,74. This may indicate that multifaceted STIM2 exert
activated and regulated by a wide variety of stimuli, such as Ca2þ,
specific functions in different types of cancer.
temperature, pH, ROS, chemical and mechanical stress. As such, they
Compared with Orai1, much less is known about Orai2 and Orai3
are perfect candidates for cellular sensors and are believed to actively
in malignant diseases. Except up-regulated in non-small cell lung
participate in the tumor–microenvironment cross-talk48.
cancer (NSCLC) and contributed to cell proliferation and tumor grades,
As summarized in Table 1, a large number of TRP members
Orai3 is also overexpressed in breast cancer tissues, cell lines MCF-7
present altered expression and/or channel activity in a variety of
and T47D as respectively compared to adjacent normal tissues and
cancers. For example, the presence of the TRPC, TRPM, and
non-cancerous cell line MCF-10A75,76. Motiani et al.77,78 showed that
TRPV subfamilies correlates with malignant growth and cancer
abnormal SOCE was mediated by Orai3 in estrogen-receptor-positive
progression49–53. TRPM7, 8 and TRPV2, 6 are associated with the
breast cancer lines and this increased the proto-oncogenes NFAT
prostate cancer progression and TRPC6 as a novel therapeutic
transcriptional activity through MAP kinase pathway. Orai3 and Orai1
target for esophageal carcinoma18,54–58. In breast cancer, TRPC1,
form arachidonate-regulated Ca2þ entry channel and their ratio
TRPC6, TRPM7, TRPM8, and TRPV6 are overexpressed, and
represents an oncogenic switch, which facilitates proliferation and
their expression profiles are associated with pathologic parameters,
apoptotic resistance in prostate cancer68. More detailed discussion on
suggesting their use as prognostic markers53,59. The expression
recent advances in SOCE and its contribution to cancer can be found in
profile of TRPM7/8 depends on both invasive and hormonal
our review article published elsewhere79.
status: in non-invasive estrogen-positive cells, TRPM7 is highly
expressed and mediates Ca2þ influx, which results in proliferation
and poor differentiation60; on the other hand, TRPM8 is highly 2.3.4. Purinergic receptors
expressed in non-invasive well-differentiated estrogen-positive Purinergic signaling receptors for extracellular nucleotides (P1 and
breast cancer, and may serve as a good prognostic marker for this P2 receptors) are widely expressed by mammalian cells. The P2
type cancer61; in aggressive estrogen-negative cancers, they receptors are divided into P2X and P2Y groups and each group
regulate cell migration through an interaction with cytoskeleton contains several members with distinct ion selectivity and reg-
proteins62. Besides mentioned above, there are still some of other ulatory properties. Numerous studies have demonstrated that P2
TRP family proteins involved and contributed to cancer develop- receptors involve in cancer cells and are expressed to a very high
ment, which were summarized in Table 1. Therefore the level in some cases, such as P2X3, P2X5, P2X7 and P2Y2 and
P2Y442,80–83 (Table 1). In terms of clinical evaluation, P2X3 H+/Ca2+ exchangers (HCX)86. A wide variety of studies reported
receptor overexpression was reported to be associated with poor the involvement of these mitochondrial Ca2þ handling proteins in
recurrence-free survival in hepatocellular carcinoma patients84. cancer cell metabolism, apoptosis and proliferation. Overexpres-
sion of MCU is reported in the clinical estrogen receptor negative
2.4. Mitochondrial Ca2þ uniporter and basal-like breast cancer samples87. However, down-regulation
of MCU in colon and prostate-derived cancers has been shown to
Mitochondria are capable for rapid Ca2þ uptake and thus actively promote increased proliferation and bestows resistance to cell
shape the overall intracellular Ca2þ signaling. Their Ca2þ uptakes death stimuli through diminished mitochondrial Ca2þ levels88.
are mediated largely by mitochondrial Ca2+ uniporter (MCU) and Down-regulation of MICU1, which results in mitochondrial Ca2þ
regulated by a gate keeper protein mitochondrial Ca2+ uptake 1 overload, did not alter proliferation in HeLa cells; however, it
(MICU1)85. The accumulated mitochondrial Ca2þ ions are quickly triggers excessive mROS generation and significantly enhances
pumped back to cytosol by mitochondrial NCX and mitochondrial sensitivity to apoptotic stress85,89.
Table 1 Altered Ca2þ channels/transporters/pumps in cancers.
Channel/transporter Cancer type Changes Ref.
IP3R IP3R1 Glioma Decreased 24

IP3R2 Lymphocytic leukemia Increased 28
IP3R3 Glioma, gastric, colon, head and neck cancer Increased/Mutation 24–27
Ca2þ-ATPase SERCA2 Colon cancer Increased 32

SERCA3 Gastric, lung, choroid plexus tumors, and in myeloid leukemia Decreased 31
SPCA1 Breast cancer Increased 35
SPCA2 Breast cancer Increased 36
PMCA1 Oral cancer Decreased 39
PMCA2 Breast cancer mRNA elevated 37
PMCA4 Colon cancer Decreased 38
VGCC Cav1.2 Colon and esophageal cancer Increased 42

Cav2.3 Glioma Increased 42
Cav3.1 Glioma Increased 46
Cav3.2 Prostate, ovarian, glioma, breast, esophageal, hepatoma, Increased 42–45
melanoma, and colon cancer
TRP TRPC1 Breast cancer Increased 49

TRPC3 Ovarian and breast cancer Increased 50, 51
TRPC6 Esophageal, glioma and breast cancer Increased 51, 57, 90
TRPM1 Melanoma Decreased 91
TRPM7 Pancreatic and breast cancer Increased 60, 92
TRPM8 Pancreatic, prostate, bladder, breast, melanoma, colon and Increased 58,92, 93
lung cancer
TRPV1 Bladder and prostate cancer Decreased/Increased 94, 95
TRPV2 Bladder, prostate cancer and hepatocarcinoma Decreased/Increased 96
TRPV4 Non-melanoma skin cancer, tumor endothelial cell derived Decreased 97–99
prostate and breast cancer
TRPV6 Breast, prostate, lung, thyroid, colon and ovarian cancer Increased 100–103
Orai & STIM Orai1 Pancreatic adenocarcinoma, glioma, melanoma, breast, Increased/Constitutive 6, 36, 65, 66, 74,
esophageal, renal, and NSCLC activated 104–106
Orai3 Breast, prostate and lung cancer Increased 68, 76, 78
STIM1 Hepatoma, melanoma, cervical, colorectal cancer, breast and Increased 66, 69, 104, 107–
pancreatic adenocarcinoma 109
STIM2 Breast, colorectal cancer and melanoma Increased/Decreased 73,74,109, 110
Purinergic P2X3 Hepatoma Increased 84

receptor P2X5 Melanoma, colorectal, brain, breast and renal cancer Increased 42
P2X7 Neuroblastoma, melanoma, leukemia, breast, prostate, papillary Increased 42,80
thyroid, pancreatic, colon, renal, cervical and B chronic cancer
P2Y2 Highly metastatic breast cancer, hepatoma and colon cancer Increased 81–83
P2Y4 Colon cancer Increased 83
MCU Breast, colon and prostate cancer Decreased/Increased 87,88

3. Drugs targeting Ca2þ channels/transporters/pumps for treatment42. In fact, as early as in 1990s, some structurally
cancer treatment unrelated L-type VGCCs antagonists were tested for their potent
inhibitory effects on breast tumor progression190. The dihydropyr-
The complexity of widespread Ca2þ channels/transporters/pumps idine Ca2þ channel blocker, amlodipine, was found to inhibit the
with the diverse activation process, offers an abundance of growth of human epidermoid carcinoma A431 cells both in vitro
potential targets for pharmacological regulation and cancer che- and in vivo, via arresting cell cycle at G1 phase and reducing
motherapy. Progress in understanding of the intracellular Ca2þ phosphorylation of retinoblastoma protein, expression levels of
signaling network, especially the channels/transporters/pumps cyclin D1 and cyclin dependent kinase 4120. Another interesting
structure, has significantly advanced the field of drug design and case is mibefradil, a T- and L-type Ca2þ channel blocker used for
development with particular focus on potentials and specific anti-hypertensive. It was later voluntarily withdrawn from market
selectivity inhibitor or regulator. In this section, we attempt to due to its side effect of inhibiting cytochrome P450 enzymes 2D6,
summarize the known compounds or antibodies targeting these 3A4 and p-glycoprotein. However, mibefradil was shown to be
above mentioned cancer-involved Ca2þ channels/transporters/ able efficiently to reduce tumor size, to improve the survival rate in
pumps, which have been studied in pre-clinical research or even glioma animal model as well as in a patient derived pancreas
in clinical trials (Table 2). A certain number of these compounds xenograft animal model42,121. Therefore, mibefradil was repur-
have been demonstrated with promising ability to be used in posed for pancreatic cancer and high-grade glioma therapy. FDA
cancer therapy. swiftly approved mibefradil as an orphan drug for pancreatic
cancer treatment in 2008 and its use for glioma treatment has also
been moved into clinical trial191. Moreover, a mibefradil derived
3.1. Ca2þ-ATPase inhibitors
novel compound, NNC-55-0396, was developed to selectively
target Ca2þ channel and exhibits less inhibitory effect on
The sustained high cytoplasm Ca2þ is toxic for cells by activating
cytochrome P450 3A4. This new derived mibefradil compound
cell death signaling4. Ca2þ-ATPases can be easily targeted by
appears to be a promising chemotherapy drug for that it is able to
shutting-down of these pumps to generate such toxic cytosolic
effectively inhibit angiogenesis in cancer cell lines but with
Ca2þ concentrations for either apoptosis or necrosis. A PMCA
minimal off-target effect42,119.
selective inhibitor [Pt(O,O0 -acac)(γ-acac)(DMS)] is used to rapidly
induce apoptosis in MCF-7 cells, which may induce ROS in
addition to cytosol Ca2þ elevation117. Our earlier work showed 3.3. TRP channel regulators
that the depletion of ER Ca2þ stores itself is sufficient to cause ER
stress and to induce programmed cell death pathways188. A
The imidazole compound SKF-96365 and related antimycotic
selective inhibitor of SERCA pump, thapsigargin (TG), is used
compounds including econazole, miconazole, and clotrimazole can
to inhibit Ca2þ uptake into ER and deplete ER Ca2þ stores. The
inhibit CRACs and some TRP channels192. While SKF-96365 was
application of TG as chemotherapeutic agent has been extensively
firstly described to block receptor-mediated Ca2þ entry in human
studied in prostate cancer and other cancers14,112. However, a
platelets, neutrophils and endothelial cells193, it later was used to
barrier preventing the direct usage of TG as clinical effective drug
inhibit ovarian cancerous cell growth and tumorigenesis via
is its non-selectivity since TG will destroy intracellular Ca2þ
reducing activities of different subtypes of TRPCs194. Treatment
homeostasis not only in cancer cells but also in normal cells. Thus
of SKF-96365 was reported to enhance radio-sensitization in
the research effort on development of TG as chemotherapy drug
glioblastoma, which contain high expressing levels of TRPC6
has been focused on tumor targeting. One successful example is
channels90. In addition, SKF-96365 can also cause cell cycle arrest
G202, in which an analogue to TG is conjugated to prostate-
at S and G2 phases in glioblastoma cells via enhancing reverse
specific membrane antigen (PSMA) targeting peptide. PSMA is a
mode of the NCX1, independent of TRPCs181.
type II membrane carboxypeptidase and is overexpressed in
Using a structure-based design, a synthetic compound TH-1177
prostate cancer cells and most tumor endothelial cells, but not in
mimicking dihydropyridines was developed as a TRPV channel
normal vasculature or normal tissue epithelium. As a prodrug,
blocker. It inhibits prostate cancer cell proliferation in vitro and
G202 itself is non-toxic since it cannot enter the cell due to its size.
in vivo154. However, there is one issue preventing TH-1177 from
Once it reaches tumor, it binds with PSMA and subsequently
further clinical application. It preferentially inhibits TRPV5 but less
PSMA can cleave the peptide and release active cytotoxic analog
effective for TRPV6 channel; whereas TRPV6 is the most abundant
of TG. G202, later termed as mipsagargin, significantly inhibits
Ca2þ entry channel in prostate cancer cells with its expression level
tumor progression including prostate, breast and bladder cancers,
as high as 45-fold more than TRPV5. Thus, TH-1177 was further
while presenting minimally toxicity to the host animals112. G202
modified to possess high selectivity for TRPV6 and this new agent
has showed promising results in several pre-clinical studies and is
has been demonstrated significantly improved inhibitory effects on
currently in phase II clinical trial for prostate cancer and
cell proliferation in prostate and breast cancer152.
progressive glioblastoma.
GSK1016790A is a selective TRPV4 channel agonist devel-
oped recently. It is at least 300-fold more potent than the
3.2. Voltage-gated Ca2þ channel inhibitors commonly used TRPV4 activator 4α-PDD142. TRPV4 is able to
regulate tumor angiogenesis and vessel maturation, thus
The first well-studied family of compounds targeting Ca2þ GSK1016790A has been proposed to be used together with other
signaling are the inhibitors for VGCCs, which are widely used anticancer drugs, such as cisplatin, to improve tumor penetration
in the cardiovascular or nervous system diseases189. As accumu- for more effective cancer therapy98. By mimicking the C-terminus
lating evidences reveal the important roles of VGCCs in a number of soricidin, two TRPV6 inhibitors, the SOR-C13 and SOR-C27
of cancers, many investigators have launched the studies to bind TRPV6 with high affinity in ovarian cancer cells. SOR-C13 is
repurpose the FDA approved drugs targeting VGCCs for cancer currently in phase I clinical trial for advanced cancers, in which
Targeting calcium signaling in cancer therapy
Table 2 Summary of compounds targeting Ca2þ channels/transporters/pumps.
Channel/Transporter Compound Mechanism Cancer Ref.
Ca2þ-ATPase SERCA Cyclopiazonic acid, thapsigargin, G202, KP1019 Saikosaponin-d, Alisol B Inhibitor Prostate, hepatoma, colon, cervical, breast 111–115
cancer and nasopharyngeal
SERCA2 RL71 Inhibitor Colon cancer 116
PMCA [Pt(O,O0 -acac)(γ-acac)(DMS)] Inhibitor Breast cancer 117
VGCC T-type KYS05047, mibefradil, NNC-55-0396, amlodipine Blocker Hepatoma, lung pancreatic cancer, 118–121
epidermoid carcinoma and glioma
T-type Ghrelin Increase protein Prostate cancer 122
expression
TRP TRPA1 HC-030031 Inhibitor – 123
Polygodial and analog Activator Glioma, melanoma, uterine, lung and 124
breast
cancer
TRPC 20-GPPD Activator Colon cancer 125
TRPC SKF96365, M804 Blocker Glioma 126,127
TRPC1 EVP4593 Inhibitor Neuroblastoma 128
TRPC4/5 ( )-Englerin A Activator Renal and colon cancer 129,130
TRPC4/5 M804 analog, ML204 Inhibitor – 126,131
TRPC3/6 GSK2332255B, GSK2833503A Inhibitor – 132
TRPC6 GaQ3 Induce protein Breast, lung, osteosarcoma and hepatoma 133
expression
TRPV CPZ Inhibitor OSCC 134
TRPV1 CBD, Capsaicin Agonist Colon cancer, renal carcinoma. 135–138
TRPV2 2-APB, cannabinoid, lysophospholipid and probenecid Agonist Glioblastoma, bladder cancer 96,139,140
Ruthenium red, TEA, TRIM, 4-aminopyridine, SKF96365 and tranilast Antagonist Breast cancer 96,139,141
TRPV4 GSK1016790A Agonist Prostate cancer 98,142
GSK2193874, RN-9893, BTP2 Inhibitor – 143–145
TRPM8 CBG, M8-B Inhibitor Lymphoma, lung, breast, prostate and skin 146–148
pancreatic,
D-3263 Agonist Various advanced cancer 93,149
TRPML ML-SA1 Agonist – 150
TRPML1 MK6-83 Agonist – 151
TRPV6 TH-1177, Soricidin, SOR-C13 and SOR-C27 Inhibitor Ovarian, prostate and brain cancer 152–154
Orai CRAC Carboxyamidotriazole, dihydropyridine, MRS-1844, MRS-1845, BTP2 Inhibitor Hepatoma, lung, bladder, kidney, NSCLC, 155–159
glioma and leukemia
STIM1 ML-9 Translocation inhibitor Prostate Cancer 160,161
Orai1-STIM1 SKF96365 Inhibitor Esophageal, breast and colon cancer 6,64,108
Orai1 La3þ, Gd3þ, AnCoA4, SB01990, SPB06836, KM06293, RH01882, GSK- Inhibitor Lung cancer and glioma 65,162–166
5503A, GSK-7975A, mAbs
– 2-APB and its analogues, DPB-162AE and DPB-163AE Inhibitor/Activator Colon cancer and glioma 65,108,167,168
– RO2959 Inhibitor – 169
9
TRPV6 channels are normally overexpressed153. Another com-

pound in phase I clinical trial with similar mechanism is D-3263. It
is an activator for TRPM8 and induces cancer cell apoptosis,
which is proposed to be used for patients with solid tumors93.
25,185,186
175–180
Neuroblastoma, prostate and breast cancer 182–184

171,172
173,174
186,187
Capsaicin, a well-known activator for TRPV1, was shown to
Ref.
induce apoptosis by its action on TRPV6 but independent on

170
172
181
122
TRPV1, followed by activation of calpains in human small cell
lung cancer cells (SCLC) in vitro and in vivo101. TRPV antagonist
capsazepine (CPZ) was demonstrated to effectively inhibit oral
squamous cell carcinoma cells (OSCC) growth in vivo. The anti-
Colon cancer and renal melanoma
Leukemia, colon and brain cancer
cancer mechanism of CPZ may also rely on ROS release,

independent of TRPV1134. Subcutaneous injection of either
Colon cancer and glioma

capsaicin or CPZ significantly suppresses PC-3 tumor growth by
inducing apoptosis of tumor cells in vivo, suggesting they are
Breast and prostate
promising chemotherapy drugs195. Sesquiterpene ( )-englerin A

Prostate cancer
Prostate cancer
is a selective and potent activator for TRPC4 and TRPC5, which

Gastric cancer
results in massive Ca2þ influx followed by cell death and retarded

tumor cell growth129,130. However, its severe lethal side effect
Glioma
Cancer
must be resolved before it can be considered as a potential

–
therapeutic agent. The natural compound, 20-GPPD, a metabolite

of ginseng saponin, induces TRPC-mediated Ca2þ influx and
apoptosis in CT-26 cells and reduces tumor mass by 75% in vivo
Increase protein
although the exact molecular target remains unknown125. Some

cannabinoid compounds, in particular cannabidiol (CBD), stimu-
expression
Mechanism
Enhancer
Inhibitor
Inhibitor
Inhibitor
Inhibitor
Inhibitor
Inhibitor
late TRPV1 while the non-psychotropic cannabigerol (CBG) is an

Agonist
Blocker
antagonist of TRPM8146. CBD displayed anti-invasive action in

human lung carcinoma A549 cells, dependent on the effect of
CBD cannabinoid receptor and TRPV1196.
ORM-10103, KB-R7943, OSW-1, DMS, bepridil and benzothiazepine
AZ10606120, A-740003, A-438079, brilliant blue G, oxidized ATP
3.4. Orai inhibitors

analogues, such as diltiazem, clonazepam and CGP-37157
Among many known compounds targeting CRAC or SOCE, the

Orai channel blockers are particularly well studied. Because
CRAC channels present highly selective Ca2þ conductance, they
are subject to blockage by the trivalent ions La3þ and Gd3þ. Both
La3þ and Gd3þ can directly block CRAC pore formed by the I–II
4-Chloro-m-cresol, caffeine and its analogs
loop region of Orai1. However, this effect is not specific for

CRAC, as La3þ and Gd3þ also block other Ca2þ channels as well,
such as Cav, TRP channel and PMCA162,163,197.
Xestospongin B, xestospongin C
The first Orai1 inhibitor used in cancer study is SKF-96365.

Yang et al.64, demonstrated that SKF-96365 can inhibit breast
cancer cell migration in vitro and reduce tumor growth and
metastasis in vivo. We also showed that SKF-96365 inhibited
Orai1-mediated SOCE and intracellular Ca2þ oscillations in
A-317491, AF-353
Heparin, caffeine
esophageal cancer cells and resulted in significant retarded tumor

growth in nude mice6.
Compound
SKF96365
Another commonly used SOCE inhibitor is 2-APB, which was

Suramin
Ghrelin
2-APB
initially identified as a noncompetitive antagonist of IP3R (at rather

high concentration 100 μmol/L)185. The effects of 2-APB on
SOCE are multifaceted. On one hand, 2-APB inhibits Orai1
current without interrupting STIM1 and Orai1 interaction198; on
P2X2/3
the other hand, it can directly activate Orai3 channel independent

IP3R1
IP3R3
P2X7
on store depletion or STIM1199,200. There is also a dose-dependent

–
–
Channel/Transporter
bimodal effect of 2-APB on SOCE, with strong enhancement at

Table 2 (continued )
low doses (o5 μmol/L) and transient enhancement followed by

inhibition at high concentrations (420 μmol/L)167,201. Although
–Not Known
Purinergic
several studies demonstrated that 2-APB effectively inhibit cancer

receptor
cell proliferation and tumor progression, the non-selective and

NCX
IP3R
RyR
multiple-target nature renders 2-APB unsuitable for chemother-

apy25,108. Much effort has been devoted to develop 2-APB derived
compounds to overcome the obstacle. For example, DPB-162AE
and DPB-163AE are constructed as dimers of 2-APB. They are than the pyrazole ring in BTP2207. Compared with BTP2 and the
over 100-fold more potent than 2-APB on SOCE inhibition, GSK compounds, the speed of inhibition by Synta 66 is rather
without affecting IP3R function at such concentrations168. Never- slow. It requires pre-incubation with cells for more than 1 h and its
theless, there will be a long journey before such compounds can be effect is poorly reversible. These data suggest that the pore
developed as effective chemotherapeutic drug. blocking mechanism is unlikely the case for Synta66. Moreover,
Another line of research is screening of small-molecule Synta66 has no effect on STIM1 puncta formation, suggesting that
compounds that bound to Orai1 and/or STIM1 in a microarray it does not inhibit the early steps of STIM1 activation and
system containing minimal functional domains of STIM1 and translocation to junctional ER-PM sites208. CM2489 and
Orai1. Some novel STIM–Orai inhibitors have been identified CM3457 are another two promising inhibitors for SOCE, demon-
using this high-throughput screen approach, such as AnCoA4. strated in lymphocytes and T cell-derived cytokine production209.
AnCoA4 inhibits CRACs and attenuates T-cell activation both in CM2489 has completed phase I clinical trials for the treatment of
in vitro and in vivo. It reduces the recruitment of Orai1 into puncta moderate-to-severe plaque psoriasis. This is the first CRAC
and also inhibits the activity of the constitutively active Orai1V102C channel inhibitor to be tested on humans and represents a
channels, independent on STIM1166. promising lead for the development of novel therapeutics for
ML-9 is an inhibitor for myosin light-chain kinase (MLCK) and human diseases, including cancers.
appears to be able to disperse STIM1 puncta, thus to inhibit SOCE. Recombinant Orai1 monoclonal antibodies (mAbs) exhibit
Although its target and mechanism of action are unclear, ML-9 is the strong and specific binding against Orai1 at amino acid residues
only known inhibitor so far to inhibit SOCE through interference 210–217 in the second extracellular loop. These mAbs, especially
with STIM1 translocation160. Later, ML-9 alone was proved to 2C1.1, inhibit ICRAC in Orai1 high expressed Jurkat T cells as well
effectively induce prostate cancer cell death associated with autop- as HEK293210. Functional assays indicate that these mAbs
hagy in a concentration and Ca2þ dependent manner. Furthermore, strongly inhibited NFAT-dependent gene transcription in Jurkat
combination of ML-9 and some existing anticancer drugs, such as cells or TG- and ionomycin-induced cytokine secretion from
docetaxel, significantly promotes cancer cell death, suggesting ML-9 human T cells. Taking a similar approach, another specific anti-
as a promising adjuvant drug for chemotherapy161. Orai1 mAb targeting the second extracellular loop, inhibits the
RO2959 is a novel, potent and selective SOCE inhibitor (IC50, proliferation of T cells and cytokine production both in vitro and
40 nmol/L). It inhibits a wide range of Ca2þ dependent cellular in vivo. Further mechanistic studies suggested that mAb-targeted
functions including gene expression, cytokine production, and Orai1 proteins are internalized, which resulting in loss of func-
proliferation in T cells. To achieve the IC50 values at nmol/L level, tional SOCE activity211. Although the anti-Orai1 mAbs-based
it requires pre-incubation of cells for more than 30 min, which potential therapy is limited in immune diseases, it raises high hope
suggests that RO2959 may act on Orai1 channels indirectly169. of similar application for cancer treatment.
The effect of RO2959 in cancer and molecular basis of drug
action, including whether it affects the function and choreography 3.5. Miscellaneous
of STIM1, are still unclear.
Another class of potent CRAC inhibitor is designed targeting the Many regulators targeting Ca2þ channels/transporters/pumps other
Ca2þ selectivity filter of Orai channel. In particular, E106 accounts than the above mentioned, have been used in various areas, such as
for Ca2þ selectivity in Orai1 and can be blocked by extracellular immune suppression, anti-hypertension and anti-cancer. Xestospon-
protons202. This class of inhibitor includes SB01990, SPB06836, gin B as a specific IP3R inhibitor has been demonstrated to reduce
KM06293 and RH01882, which all present the capability to alter the proliferation and colony formation ability, while induce necrotic
pore geometry of Orai1 and diminishes SOCE164. death, specifically in tumorigenic breast cells, compared with non-
Two pyrazole derivatives GSK-5503A and GSK-7975A slowly tumorigenic cell lines184. Caffeine, a RyR agonist, can induce
inhibit Orai1- and Orai3-mediated SOCE currents without affect- apoptosis in prostate cancer cells, while another agonist 4-chloro-
ing STIM1–Orai1 coupling. It takes a few minutes for the two m-cresol can inhibit the breast cancer cell growth173. Several
compounds to have effects, suggesting that the mechanism is compounds targeting NCX, such as OSW-1, showed apoptosis-
likely other than through the CRAC channel activation process165. induce function by causing mitochondrial Ca2þ overload in leuke-
The IC50 is increased 10-fold in the Orai1E106D and in 2-APB mia174. Brilliant blue G, a P2X7 antagonist, exhibits inhibitory effect
activated Orai3 channels, both of which are poorly selective for on glioma growth. Emodin, a P2X non-specific inhibitor, reduces
Ca2þ and exhibit wider pores than the Orai1WT channel165,200,203. P2X7-mediated cancer cell migration. A number of P2X7 receptor
Interestingly, these compounds also inhibit TRPV6 channels, regulators, such as antagonist A-438079 and A-740003 are mainly
possibly due to similarities between CRAC and TRPV6 channels studied in pain relief. Since the P2 receptors play important roles in a
in the target site204. The Pyr analogs, including Pyr2, 3, 6 and 10, certain number of cancers, it is reasonable to believe these
show different selectivity on TRPC3 and Orai1/STIM1-mediated antagonists may be potential effective anti-cancer drugs as well172.
Ca2þ entry. Pyr10 is potent and selective for TRPC3-mediated If that holds true, these compounds could exert dual functions as
responses (18-fold), and Pyr6 prefers Orai1/STIM1, while Pyr3 both chemotherapeutic agents and pain killer.
equally blocked the two channels205. The best-studied member of
this group is Pyr2 (also known as BTP2 or YM-58483), a potent
inhibitor for both CRAC and TRPC-mediated Ca2þ 4. Conclusion and future directions
entry127,157,206. However, it also proposed that a key mechanism
of BTP2 inhibition of Ca2þ influx and cytokine release might be It is becoming evident that Ca2þ channels/transporters/pumps are
related to its ability to depolarize the cell membrane via TRPM4 involved in a wide range of cancers. Dysregulated Ca2þ home-
activation, thereby reducing the driving force for Ca2þ entry145. ostasis may play a role more like a “driver” than a “passenger” in
Synta 66 selectively inhibits ICRAC in RBL-1 cells, which is carcinogenesis or tumorigenesis. As summarized in this review,
structurally similar to BTP2 but contains a biphenyl group rather this relatively new field has already importantly contributed to the
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Targeting Calcium Signaling in Cancer Therapy

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Acta Pharmaceutica Sinica B 2017;7(1):3–17

Chinese Pharmaceutical Association

Acta Pharmaceutica Sinica B

Targeting calcium signaling in cancer therapy

Received 21 October 2016; accepted 28 October 2016

1. Introduction research area toward evaluation of a certain numbers of Ca2þ

2.1. IP3Rs — ER Ca2þ release channels 2.2. Ca2þ-ATPases

Table 1 Altered Ca2þ channels/transporters/pumps in cancers.

Channel/transporter Cancer type Changes Ref.

IP3R IP3R1 Glioma Decreased 24

Ca2þ-ATPase SERCA2 Colon cancer Increased 32

VGCC Cav1.2 Colon and esophageal cancer Increased 42

TRP TRPC1 Breast cancer Increased 49

Purinergic P2X3 Hepatoma Increased 84

MCU Breast, colon and prostate cancer Decreased/Increased 87,88

Channel/Transporter Compound Mechanism Cancer Ref.

TRPV6 channels are normally overexpressed153. Another com-

Neuroblastoma, prostate and breast cancer 182–184

induce apoptosis by its action on TRPV6 but independent on

Leukemia, colon and brain cancer

cancer mechanism of CPZ may also rely on ROS release,

Colon cancer and glioma

promising chemotherapy drugs195. Sesquiterpene ( )-englerin A

is a selective and potent activator for TRPC4 and TRPC5, which

results in massive Ca2þ inﬂux followed by cell death and retarded

must be resolved before it can be considered as a potential

therapeutic agent. The natural compound, 20-GPPD, a metabolite

although the exact molecular target remains unknown125. Some

late TRPV1 while the non-psychotropic cannabigerol (CBG) is an

antagonist of TRPM8146. CBD displayed anti-invasive action in

3.4. Orai inhibitors

Among many known compounds targeting CRAC or SOCE, the

loop region of Orai1. However, this effect is not speciﬁc for

The ﬁrst Orai1 inhibitor used in cancer study is SKF-96365.

esophageal cancer cells and resulted in signiﬁcant retarded tumor

Another commonly used SOCE inhibitor is 2-APB, which was

initially identiﬁed as a noncompetitive antagonist of IP3R (at rather

the other hand, it can directly activate Orai3 channel independent

on store depletion or STIM1199,200. There is also a dose-dependent

bimodal effect of 2-APB on SOCE, with strong enhancement at

low doses (o5 μmol/L) and transient enhancement followed by

several studies demonstrated that 2-APB effectively inhibit cancer

cell proliferation and tumor progression, the non-selective and

multiple-target nature renders 2-APB unsuitable for chemother-

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