Development of Store-Operated Calcium Entry-Targeted Compounds in Cancer

Store-operated Ca2+ entry (SOCE) is the major pathway of Ca2+ entry in mammalian cells, and regulates a variety of cellular functions including proliferation, motility, apoptosis, and death. Accumulating evidence has indicated that augmented SOCE is related to the generation and development of cancer, including tumor formation, proliferation, angiogenesis, metastasis, and antitumor immunity. Therefore, the development of compounds targeting SOCE has been proposed as a potential and effective strategy for use in cancer therapy. In this review, we summarize the current research on SOCE inhibitors and blockers, discuss their effects and possible mechanisms of action in cancer therapy, and induce a new perspective on the treatment of cancer.


INTRODUCTION
The Overview of Store-Operated Calcium Entry Store-operated calcium entry (SOCE) is typically activated by ligands of cell surface receptors such as G proteins that activate phospholipase C (PLC) to cleave phosphatidylinositol 4, 5-bisphosphate (PIP2) and produce inositol 1, 4, 5-trisphosphate (IP3). IP3 binds to IP3 receptors (IP3R) on the endoplasmic reticulum (ER) membrane, leading to the release of Ca 2+ from the ER. Cells respond to this depletion of ER intraluminal Ca 2+ by opening Ca 2+ channels to allow cellular influx, which is also the provenance of "SOCE." Researchers have been exploring the mechanisms and functions of SOCE since its discovery and definition, and it has been found that stromal interaction molecules (STIMs) and ORAI family proteins are the two major participants in SOCE (Hogan et al., 2010;Prakriya and Lewis, 2015).
STIM proteins (STIM1 and STIM2) are located on the ER membrane and are essential for SOCE (Williams et al., 2001;Liou et al., 2005;Roos et al., 2005). STIM1 contains an ER-luminal portion (containing two EF-hands and a sterile α-motif (SAM) domain), a single transmembrane segment, and a cytoplasmic portion (containing a coiled-coil domain (CCD), a STIM-ORAI-activating region (SOAR) or CRAC activation domain (CAD), a serine-or proline-rich segments and a polybasic (PB) C-tail) (Hogan et al., 2010;Xie et al., 2016). STIM2 has a structure similar to STIM1 but a critical residue difference in the SOAR domain, which endows STIM2 with partial agonist properties and competitive inhibiting functions in STIM1-mediated Ca 2+ entry, thereby maintaining basal cytoplasmic Ca 2+ levels by preventing uncontrolled activation of ORAI proteins (Brandman et al., 2007;Wang et al., 2014).
ORAI proteins are plasma membrane (PM) channels that can be gated by STIMs for Ca 2+ entry during SOCE. Three homologs of ORAI have been identified in humans, namely, ORAI1, ORAI2, and ORAI3 (also called CRACM1-3), among which, ORAI1 is the most potent and has been extensively studied. ORAI1 contains four transmembrane helices (TM1-TM4), an intracellular location domain (including N-terminal and C-terminal epitope tags) and an extracellular location domain (including an epitope tag introduced into the TM3-TM4 loop). The N-terminus and C-terminus of ORAI1 intracellular sites are essential for the interaction with STIM1 and the opening of the ORAI1 channel Vig et al., 2006;Hogan et al., 2010;Xie et al., 2016). The homologs, ORAI2 and ORAI3 primarily differ in cytosolic N-terminal, C-terminal and 3-4 loop sequences (Amcheslavsky et al., 2015), and they mediate SOCE in a manner similar to that of ORAI1, but they differ in permeability properties and inactivation (Lis et al., 2007), leading to augmented SOCE efficacy in the order ORAI1 > ORAI2 > ORAI3 (Mercer et al., 2006). When STIM1 residing in the ER lumen senses a Ca 2+ decrease in the ER, it initiates conformational changes and oligomerization, overcoming the intracellular autoinhibition mediated by CC1 to expose SOAR/CAD and the PB C-tail. Activated STIM1 multimerizes and migrates toward the PM, where it interacts with the intracellular regions of ORAI1, resulting in ORAI1 activation and Ca 2+ influx ( Figure 1) (Liou et al., 2005;Park et al., 2009;Yuan et al., 2009;Zhou et al., 2010).
Transient receptor potential proteins (TRPs) contain similar structures, consisting of six transmembrane-helical domains (TM1-TM6) with a loop between TM5 and TM6 and cytoplasmic N-and C-termini (Venkatachalam and Montell, 2007). TRP channels, especially TRPC channels, have been proposed as candidate components of SOCE, although this assignment is still disputed, under certain conditions, several TRPC channels can function in SOCE pathways (Prakriya and Lewis, 2015). For example, in HEK-293 cells, the knockdown of TRPC1, TRPC3 or TRPC7 dramatically reduced the SOCE activated by passive Ca 2+ store depletion, while inhibition of TRPC4 or TRPC6 had no effect on SOCs activity (Zagranichnaya et al., 2005). However, in human corneal epithelial cells, mouse endothelial cells and mouse mesangial cells, TRPC4 deficiency decreased SOCE (Tiruppathi et al., 2002;Wang et al., 2004;Yang et al., 2005). Furthermore, TRPC3 and TRPC7 effects on SOCE depend on their expression levels. At low expression levels, they are activated by passive Ca 2+ store depletion and act as SOCE, while at high expression levels, they behave as Ca 2+ store-independent Ca 2+ influx channels (Worley et al., 2007). Therefore, it is necessary to continue to explore the function of TRPCs in SOCE.

Role of Store-Operated Calcium Entry in Cancer
Accumulating evidence has revealed that many cancers, such as breast, liver, lung, gastric, colon, and ovarian cancer, exhibit augmented SOCE and overexpression of STIM1 or ORAI1. SOCE inhibition through STIM1 or ORAI1 knockdown inhibits the proliferation and metastasis of cancer cells, suggesting that SOCE may act as an oncogenic pathway (Yang et al., 2009;Chen et al., 2011;Yoshida et al., 2012;Motiani et al., 2013;Yang et al., 2013;Zhang et al., 2013;Kim et al., 2014;Umemura et al., 2014;Wang et al., 2015;Xu et al., 2015;Schmid et al., 2016;Xia et al., 2016;Goswamee et al., 2018;Zang et al., 2019;Huang et al., 2020). In addition, SOCE is believed to promote tumor angiogenesis through the increased secretion of VEGF by Compound Structure endothelial and cancer cells. For example, in cervical cancer, STIM1 regulates the production of VEGF to control the formation of blood vessels, and the formation of tumor could be impaired by inhibiting STIM1 . In addition, the potential therapeutic value of targeting SOCE in cancer has further been supported by the fact that STIMand ORAI-mediated SOCE is essential for the secretion of cytokines and chemokines from T cells, mast cells, and macrophages, as well as in the differentiation and functions of CD4 + and CD8 + T cells. For example, the inhibition of SOCE by genetic deletion of ORAI1, STIM1, or STIM2 in murine CD4 + T cells impaired Th17 cell function, causing a decrease in the production of IL-17, which is believed to be proinflammatory factor important for tumor progression (Ma et al., 2010;Shaw et al., 2014;Mehrotra et al., 2019). Moreover, as candidate components of SOCE, TRP channels have been found to affect the survival, proliferation, and invasion of cancer cells (Shapovalov et al., 2016). For example, TRPC1 was confirmed to play different roles in tumorigenesis, inhibition of TRPC1 by siRNA or SOCE inhibitors could suppress the proliferation and invasion of cancer cells including nasopharyngeal carcinoma, malignant glioma and Compound Structure non-small-cell lung carcinoma (Bomben and Sontheimer, 2010;He et al., 2012;Tajeddine and Gailly, 2012).
In summary, SOCE promotes the proliferation and metastasis of cancer cells, and enhances tumor angiogenesis and the formation of a tumor-promoting inflammatory environment.
In addition, SKF 96365 could also effectively inhibit the metastasis of cancers. It could impair the assembly and disassembly of focal adhesions of breast cancer cells (Yang et al., 2009), block the formation and activity of invadopodium in melanoma cells (Sun et al., 2014), and it could also inhibit cell migration by inactivating non-muscle myosin II and reducing actomyosin formation and contractile force in cervical and non-small cell lung cancer (NSCLC) cells (Chen Y.-T. et al., 2013;. In addition to inhibiting growth and colony formation independently through the blockage of Ca 2+ channels, for example, through the blockage of TRPC channels in glioma cells (Bomben and Sontheimer, 2008;Ding et al., 2010;Song et al., 2014), SKF 96365 could also enhance the sensitivity of glioma cell lines to irradiation (Ding et al., 2010), suggesting that SKF 96365 may be developed not only as an anti-chemotherapy, but also as an adjuvant drug for radiotherapy.
In summary, the antineoplastic effects of SKF 96345 are universal. However, it has been confirmed that its effects are nonspecific (Franzius et al., 1994), and therefore it is necessary to conduct more studies to clearly delineate its specific mechanisms.
These effects suggest that 2-APB is attractive as a potentially potent therapy for primary cancer and metastatic cancer.

2-Aminoethoxydiphenyl Borate and Analogs
As 2-APB is a promising but not entirely specific SOCE inhibitor, Goto et al. explored two novel 2-APB structurally isomeric analogs in order to develop more specific and potent SOCE inhibitors: DPB-162AE and DPB-163AE . These two diphenylborinate (DPB) compounds are 100-fold more potent than 2-APB, and they are able to inhibit the clustering of STIM1 and block the ORAI1 or ORAI2 activity induced by STIM1 by inactivating the SOAR domain in STIM1. In particular, DPB-162 AE could consistently inhibit endogenous SOCE regardless of whether the concentration was high or low and exerted little effect on L-type Ca 2+ channels, TRPC channels, or Ca 2+ pumps when exerting maximal inhibitory effect on Ca 2+ entry Hendron et al., 2014;Bittremieux et al., 2017). However, the actions of DPB-163AE are more complex, showing a similar pattern to 2-APB by activating SOCE at low concentrations and inhibiting SOCE at higher levels .
Moreover, similar to 2-APB, at low concentrations (∼100 nM), both DPB-162AE and DPB-163AE could facilitate Orai3 currents, and at high concentrations (>300 nM), they transiently activated ORAI3 currents and then deactivated them. DPB compounds have been proven to activate ORAI3 in a STIM1-dependent manner, but they could not change the pore diameter of ORAI3, which is different from the mechanisms of 2-APB. It is speculated that because they are larger than 2-APB, DPB compounds are unable to enter the pore of ORAI3 Hendron et al., 2014). In addition, DPB-162AE was reported to provoke leakage of Ca 2+ from the ER into the cytosol in HeLa and SU-DHL-4 cells at concentrations required for adequate SOCE inhibition Bittremieux et al., 2017).
Although there have been no studies on DPB compounds with respect to cancer treatment to date, considering the specific inhibition of SOCE, DPB compounds are expected to be developed as potential anticancer drugs.

Pyr2 (N-[4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl] phenyl]-4-Methylthiadiazole-5-Carboxamide)
Pyr2, also known as BTP2 or YM-58483, was initially found to be able to inhibit SOCE, leading to impaired IL-2 production and NFAT dephosphorylation in Jurkat cells without affecting the T cell receptor (TCR) signal transduction cascade (Ishikawa et al., 2003). BTP2 also showed complicated effects on TRP channels, TRPC1, TRPC3, TRPC5, and TRPC6 channels were inhibited effectively; however, TRPM4 was activated by BTP2 at low concentrations in a dose-dependent manner. BTP-mediated facilitation of TRPM4, which is a Ca 2+ -activated cation channel that decreases Ca 2+ influx by depolarizing lymphocytes, is the main mechanism for the suppression of cytokine release. Furthermore, it has been reported that the mechanism of inhibiting TRP channels, such as TRPC3 and TRPC5, involved in reducing their open probability rather than changing their pore properties without affecting the other Ca 2+ signals in T cells including Ca 2+ pumps, mitochondrial Ca 2+ signaling and ER Ca 2+ release (Zitt et al., 2004;He et al., 2005;Schwarz et al., 2006;Takezawa et al., 2006;Oláh et al., 2011;Wu et al., 2017).
BTP2 has exhibited inhibitory effects on several types of allergic inflammation, including autoimmune and antigen induced diseases through the suppression of cytokine release (IL-2, IL-4, IL-5, TNF-α, and IFN-γ) and T cell proliferation (Ohga et al., 2008;Law et al., 2011;Geng et al., 2012). Although many studies have indicated that BTP2 affects cancer through the modulation of immune cells, previous reports have mainly focused on the direct inhibition of cell proliferation, migration, and invasion of cancer cells themselves. For example, in colon cancer, BTP2 obviously decreased cell growth through direct SOCE inhibition (Núñez et al., 2006). BTP2 could also inhibit cell migration of cervical cancer, rhabdomyosarcoma (RMS), and breast cancer via blockage of SOCE (Chen Y.-T. et al., 2013;Schmid et al., 2016;Azimi et al., 2018); furthermore, the inhibition of cell migration in cervical cancer was due to the inhibition of actomyosin reorganization and contraction forces, similar to the effects of SKF96365 and 2-APB (Chen Y.-T. et al., 2013). It was also found that BTP2 could inhibit the proliferation and tubulogenesis of endothelial progenitor cells (EPCs), which are essential for the vascularization and metastatic switching of solid tumors (Dragoni et al., 2011;Lodola et al., 2012). On the other hand, BTP2 could inhibit the invasion of prostate cancer cells by impeding the binding of drebrin to actin filaments, with a SOCE independent mechanism (Dart et al., 2017).
In summary, the mechanism and effect of BTP2 on cancer are multi-aspect, and it is necessary to carry out further research on them for clarification.

Pyr3 (Ethyl1-(4-(2,3,3-Trichloroacrylamido)phenyl)-5-(Trifluoromethyl)-1h-Pyrazole-4-Carboxylate)
Pyr3 has mainly been recognized for directly and selectively inhibiting TRPC3 with attenuated activation of Ca 2+dependent signaling pathways, and structure-function relationship studies showed that the trichloroacrylic amide group is important for the TRPC3 selectivity of Pyr3 (Kiyonaka et al., 2009). The blockade of TRPC3-mediated Ca 2+ signaling pathways by Pyr3 reduced cell proliferation, induced cell apoptosis and sensitized cell death to chemotherapeutic agents in triple-negative breast cancer through the inhibition of TRPC3-Ras GTPase-activating protein 4 (RASA4)-MAPK signaling cascade . In melanoma, Pyr3 also decreased the cell proliferation and migration in vitro and inhibited tumor growth in vivo by inhibiting TRPC3 and its downstream JAK/STAT5 and AKT pathways (Oda et al., 2017). Chang et al. reported that Pyr3 could inhibit the migration and invasion of glioblastoma multiforme (GBM) cells and reduce the size of tumor xenografts significantly by dephosphorylating focal adhesion kinase and myosin light chain . Subsequently, Pyr3 was found to effectively inhibit ORAI1-mediated SOCE in HEK293 cells and mast cells (RBL-2H3) in a dose dependent manner, and the amidbond linked side-group pivotal for TRPC subtype selectivity was also proposed as a potential structural determinant for the SOCE inhibitory action (Schleifer et al., 2012).

phenyl]methyl]pyrazol-3-yl]benzamide)
Several novel pyrazole compounds including GSK-5503A, GSK-7975A, and GSK-5498A have been developed by GlaxoSmithKline as specific blockers of SOCE. GSK-5503A and GSK-7975A could inhibit STIM1-mediated ORAI1 and ORAI3 currents potentially via an allosteric effect on the selectivity filter of ORAI with a slow onset of action that did not have effects on STIM1-STIM1 oligomerization or STIM1-ORAI1 coupling (Yamashita et al., 2007;Derler et al., 2013). GSK-7975A could also efficiently inhibit the TRPV6 channel, possibly due to its architectural similarities to the selectivity filters of ORAI channels (Owsianik et al., 2006;Derler et al., 2013;Jairaman and Prakriya, 2013). GSK-5498A and GSK-7975A have been used to inhibit mediator and cytokine release from mast cells and T cells (such as IFN-γ and IL2) in multiple human and rat preparations by completely inhibiting SOCE (Rice et al., 2013). Although the roles of immune cells and cytokines are complicated in the tumor microenvironment, these compounds are expected to be applied as cancer treatments that function through anticancer immunity processes under certain circumstances.

Synta66 (N-[4-(2,5-Dimethoxyphenyl) phenyl]-3-Fluoropyridine-4-Carboxamide)
Synta66, also known as GSK1349571A, has garnered extensive attention in recent years because of its ability to selectively inhibit CRAC channels without affecting on PDGF-or ATP-evoked Ca 2+ release, overexpressed TRPC5 channels, native TRPC1/5containing channels, STIM1 clustering or nonselective storeoperated cationic currents (Li et al., 2011). It has been confirmed that the potency of SOCE inhibition is directed against Orai1 in the order of Synta66 > 2-APB > GSK-7975A > SKF96365 > MRS1845 in human platelets (van Kruchten et al., 2012). By inhibiting SOCE effectively and specifically, Synta66 could inhibit the receptor-triggered mutual activation between Syk activation and Ca 2+ influx in the RBL mast cell line, reduce the release of histamine, leukotriene C 4 (LTC 4 ), and cytokines (such as IL-5, IL-8, IL-13, and TNF-α) in human lung mast cells (HLMCs), and inhibit the expression of T-bet and the production of IL-2, IL17, and IFN-γ in lamina propria mononuclear cells (LPMCs) and biopsy specimens obtained from inflammatory bowel disease (IBD) patients (Ng et al., 2008;Di Sabatino et al., 2009;Ashmole et al., 2012). Azimi et al. compared the pharmacological inhibitory effects of Synta66 and BTP2 on SOCE pathway in breast cancer cell lines. They found that both Synta66 and BTP2 could inhibit the protease activated receptor 2 (PAR2) activator, and trypsin and EGF produced Ca 2+ influx and serumactivated migration of MDA-MB-468 cells (Azimi et al., 2018). However, interestingly, Synta66, but not BTP2, had no effect on proliferation or EGF-activated cell migration, which are realized through unexplored mechanisms (Azimi et al., 2018). To date, no study has investigated whether Synta66 has anti-tumor effects in other cancers, nevertheless, Synta66 still has great potential to be Frontiers in Pharmacology | www.frontiersin.org May 2021 | Volume 12 | Article 688244 developed as an available therapy for tumor treatment due to its specific and effective inhibition of SOCE.

Anti-ORAI1 Monoclonal Antibodies
Lin et al. developed high-affinity fully human mAbs to human ORAI1, that bind to amino acid residues 210-217 of the human ORAI1 extracellular loop 2 domain (ECL2). These mAbs potently inhibited the SOCE, NFAT translocation and cytokine secretion from Jurkat T cells and in human whole blood (Lin et al., 2013). Another mAb to human native ORAI1, generated by Cox, also binds to ECL2 and could block the function of T cells both in vitro and in vivo, including the inhibition of T cell proliferation and cytokine production in immune cells isolated from rheumatoid arthritis patients and showed efficacy on an anti-ORAI1 human T cell-mediated graft-versus host disease (GvHD) mouse model (Cox et al., 2013), suggesting that mAb may be a novel treatment for humans with autoimmune diseases. Taken together, since anti-ORAI1 mAbs could impact on the autoimmune response, we speculate that they also show great potential to be used as cancer therapy by modulating of the tumor immune microenvironment.

RP4010
RP4010 was developed by Rhizen Pharmaceuticals. It was confirmed to block SOCE and SOCE-mediated Ca 2+ oscillations in a dose-dependent manner, leading to the inhibition of NF-κB/p65 translocation to nuclei, thus impeding the proliferation and in ESCC xenograft tumor growth (Cui et al., 2018). In pancreatic ductal adenocarcinoma, RP4010 inhibited cancer cell proliferation and colony formation by reducing Akt/ mTOR and Ca 2+ influx-mediated NFAT signaling. Furthermore, RP4010 combined with gemcitabine and nab-paclitaxel could enhance anticancer activities in PDAC cells and patient-derived xenografts, indicating the potential of RP4010 as an anticancer chemotherapy (Khan et al., 2020). Indeed, RP4010 is in phase I/IB clinical trials currently.
CM4620 (N-[5-(6-Chloro-2,2-Difluoro-1,3-Benzodioxol-5-yl)pyrazin-2-yl]-2-Fluoro-6-Methylbenzamide) CM4620, also called CM-128, was developed by CalciMedica and tested in phase I/II clinical trials to reduce pancreatitis. It could inhibit cell death pathway activation by SOCE inhibition in pancreatic acinar cells, thus leading to markedly reduced acute pancreatitis in mouse models (Wen et al., 2015). A recent study further demonstrated that in acute pancreatitis, CM4620 could not only inhibit the necrosis of parenchymal pancreatic acinar cells but could also prevent the activation of immune cells to reduce inflammation (Waldron et al., 2019). Although the effect of CM4620 on cancer cells is still unknown, it has the potential to be developed as a cancer therapy through its regulation of tumor immune cells.

Other Small Molecular Inhibitors
ML-9 (1-(5-chloronaphthalen-1-yl)sulfonyl-1,4-diazepane) was initially described as an inhibitor of myosin light chain kinases (MLCKs) that binds at or near the ATP-binding site at the active center of kinases with or without Ca 2+ calmodulin (Saitoh et al., 1987). Shortly thereafter, ML-9 was found to inhibit agoniststimulated Ca 2+ entry in endothelial cells without affecting the release of intracellular Ca 2+ stores (Watanabe et al., 1996), and it was confirmed to inhibit SOCE in a dose-dependent manner by blocking rearrangement and puncta formation of STIM1 without inhibiting MLCKs. Thus far, ML-9 is the only inhibitor of STIM1 translocation . Furthermore, ML-9 could also inhibit the activity of TRPC5 channel by impairing its plasma membrane localization through MLCK inhibition (Shimizu et al., 2006), causing apoptosis in both untransformed and transformed epithelial cells, retarding the growth of mammary and prostate cancer cells and blocking the invasion and adhesion of human pancreatic cancer cells (Kaneko et al., 2002). In another study, ML-9 reduced SOCE and induced Ca 2+ -dependent autophagy to promote the death of prostate cancer cells, but the effect of ML-9 on autophagy was independent of STIM1 and SOCE inhibition, suggesting that ML-9 may exert its effects on cancer cells through multiple mechanisms. Moreover, ML-9 combined with docetaxel could enhance the cell death of LNCaP, PC3 and DU-145 cells, suggesting that ML-9 may be developed as an adjuvant to anticancer chemotherapy (Kondratskyi et al., 2014).
NPPB (5-nitro-2-(3-phenylpropylamino)-benzoic acid), frequently used as a blocker of chloride channels, could also reduce CCE in endothelial cells (Gericke et al., 1994). It was also confirmed that NPPB could directly interact with CRAC to reversibly inhibit Ca 2+ influx in Jurkat cells in a dosedependent manner (Li et al., 2000). In ovarian cancer, NPPB could significantly inhibit A2780 cell adhesion and invasion (Li et al., 2009). AnCoA4 (3-(6-methoxy-1,3-benzodioxol-5-yl)-8,8dimethylpyrano[2,3-f]chromen-4-one) was identified by screening small-molecule microarray (SMM) using minimal functional domains of STIM1 and ORAI1, and it was found to inhibit Ca 2+ influx by binding to the C-terminus of ORAI1 directly to perturb the interaction between STIM1 and ORAI1 by reducing the affinity of ORAI1 for STIM1. Through SOCE inhibition, AnCoA4 blocked T cell activation and inhibited the T cell-mediated immune response in vitro and in vivo, indicting the possibility that it can be used in therapeutic areas, including immunomodulation, inflammation and cancer (Sadaghiani et al., 2014).
YZ129 (4-(isoquinolin-6-ylamino)-naphthalene-1,2-dione) was identified because of its inhibition of thapsigargintriggered Ca 2+ influx and NFAT nuclear entry through an automated high-content screening platform and it was found to exhibit potent anti-tumor activity against glioblastoma. It could bind to HSP90 directly and antagonize its calcineurinchaperoning effect to reduce NFAT nuclear translocation and inhibit other key proto-oncogenic pathways, including hypoxic and glycolytic pathways and the PI3K/AKT/mTOR axis, thus leading to cell cycle arrest in G2/M phase of glioblastoma and promoting apoptosis and inhibition of tumor cell proliferation and migration (Liu et al., 2019).

Repurposing FDA-Approved Drugs
In addition to the abovementioned compounds targeting SOCE, other compounds that have been approved for clinical use in corresponding diseases were confirmed to inhibit SOCE. The ability of these compounds to inhibit Ca 2+ influx through SOCE indicates the importance of learning more about their pharmacological properties and mechanisms, and the potential to extend their clinical indications.
Diethylstilbestrol (DES, 4-[(E)-4-(4-hydroxyphenyl)-hex-3en-3-yl]-phenol) is a potent synthetic estrogen used for estrogen therapy in prostate and breast cancer. It was reported to inhibit SOCE and Ca 2+ influx in a variety of cell types without affecting the whole-cell monovalent cation current mediated by TRPM7 channels. Trans-stilbene, a close structural analog of DES that lacks hydroxyl and ethyl groups, had no effect on CRAC current, further suggesting the specificity of DES for SOCE (Zakharov et al., 2004;Ohana et al., 2009;Dobrydneva et al., 2010).
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to relieve pain, fever and inflammation. Epidemiological studies worldwide have demonstrated that NSAIDs also have cancer-protective effects, as these drugs are associated with a reduced risk of various types of cancer. In colon cancer, it has been reported that NSAIDs could exert antiproliferative effects through SOCE inhibition, and salicylate, the main aspirin metabolite, is considered a mild mitochondrial uncoupler that prevents mitochondrial Ca 2+ uptake and promotes the Ca 2+ -dependent inactivation of SOCE, thus inhibiting the proliferation of HT29 cells (Núñez et al., 2006). Another study suggested that STIM1 overexpression promoted colorectal cancer progression through an increase in the expression of the pro-inflammatory and pro-metastatic enzyme cyclooxygenase-2 (COX-2). The inhibition of COX-2 with two NSAIDs, ibuprofen and indomethacin, abrogated STIM1-induced colorectal cancer (CRC) progression .

CONCLUSION AND PERSPECTIVES
Ca 2+ signaling is involved in almost all cellular activities in organisms. As a major route of Ca 2+ entry in mammalian cells for replenishing the depleted intracellular Ca 2+ store, SOCE regulates a diverse array of biological processes. Accumulating evidence has shown that STIM/ORAI-mediated SOCE is excessive in cancer tissues, and it is becoming clear that augmented SOCE promotes the malignant behavior of cancer cells, including tumor growth, angiogenesis, and metastasis. Therefore, SOCE could be a potential therapeutic target for the treatment of cancer.
As we summarized above, multiple compounds targeting SOCE have been developed and their efficiency in the inhibition of proliferation and migration of cancer cells has been evaluated. However, rare SOCE inhibitors have been approved for clinical use in cancer treatment due to their poor selectivity, which urgently needs to addressed. In addition, as SOCE is not the only channel for Ca 2+ entry, cells could adopt other ways to obtain sufficient Ca 2+ even after complete SOCE inhibition. Under this condition, drug combinations could be considered. Furthermore, due to the universal roles of Ca 2+ signaling in cells, the cytotoxicity of SOCE inhibitors on normal cells and some anticancer immune cell inhibitors should also be considered in clinical anticancer applications. Developing SOCE inhibitors that could specifically target tumor tissues in certain circumstances is a hopeful therapeutic orientation toward cancer in the future.