Cancer is the second leading cause of death globally, causing 9.6 million deaths in 2018 with an increasing estimation of 70% over the next twenty years. There are more than 100 cancer types, affecting any part of the body in both sexes. However, the most common cancer types in women are: breast (25.4%), colorectal (9.6%), lung (8.8%), cervix (6.9%) and thyroid (6.3%), meanwhile lung (15.5%), prostate (14.5%), colorectal (11.4%), liver (6.8%) and bladder (4.8%) are the most common among men (https://www.wcrf.org); (https://www.who.int). Every type of cancer is characterized by its unique clinical features, molecular markers and a disease-specific profile of genes. Nevertheless, all cancer types meet several common criteria, known as the “cancer hallmarks” described in 2000 by Hanahan and Weinberg (Hanahan and Weinberg, 2000). Although, new emerging cancer hallmarks were added in the last decade, the most accepted hallmarks are: (1) sustained proliferation, (2) cell death resistance, (3) tissue invasion and metastasis and (4) persistent angiogenesis.

Since the first hypothesis by the mid-1800s, that “canalis” are present in biological membranes (Brücke, 1847), numerous physiological functions have emerged mediated by ion channels, ranging from control cellular ionic homeostasis to sensory transduction. Consequently, ion channels perform key roles in human physiology and it is not a surprise the increasing number of evidences connecting channels disorders with a broader human diseases. Nowadays, abundant evidence demonstrate that calcium, calcium permeable channels and calcium signals, play important functions in cancer cells proliferation, apoptosis resistance, invasion and drug resistance, common cancer hallmarks. The first direct evidences connecting calcium channels and cancer were published in the 1980s, when independent studies confirmed the inhibition of cancer growth using particular calcium channels blockers (Lee et al., 1988; Batra and Alenfall, 1991; Taylor and Simpson, 1992). The ion channels research not only confirm the calcium channels correlation with cancer. Other ion channels with important roles in membrane potential or cell volume regulation, including Na⁺, K⁺ and Cl⁻ channels have been involved in the development of one or more cancer hallmarks (Pardo, 2004; Wang, 2004; Kunzelmann, 2005; Wulff et al., 2009; Schwab et al., 2012; Prevarskaya et al., 2018). At the present day, the relationship between altered expression and/or function of particular ion channels and cancer is well stablished, so well that the term “oncochannels” has been recently introduced (Huber, 2013).

This review focus in the role of calcium permeable channels signaling in cancer: from molecular mechanisms to therapeutics. Even though cancer therapies and drugs improved significantly in the last years, new and more efficient treatments are still needed to fight against such indiscriminate disease. Calcium channels and transporters are widely expressed in the plasma membrane of carcinoma cells where they may represent a good therapeutic target. For this reason, the study of ion channels role in both initial and advanced stages of the disease, should be useful to explore the possible clinical value of this membrane proteins as novel targets for therapy.

In this review we will consider the role of calcium permeable channels signaling in cancer with special attention to the mechanisms behind the remodeling of the calcium signals. The calcium channel modulators and their therapeutic use in treating cancer disease will be also discussed in the review.

Calcium permeable channels are membrane proteins located in the external and internal cell membranes, including plasma membrane (PM), and endoplasmic reticulum (ER) or mitochondria, respectively. These channels diffuse passively Ca²⁺ ions down its electromechanical gradient from extracellular space and from intracellular calcium stores to the cytoplasm. At the PM there is a wide diversity of calcium channel types, characterized by their activation mechanism: (1) Voltage-gated calcium channels (VGCCs), (2) receptor-operated calcium channels (ROCCs), (3) store-operated calcium channels (SOCCs), (4) transient receptor potential channels (TRPs), (5) acid-sensing ion channels (ASICs) and (6) stretch-activated ion channels (SAICs). VGCCs are the major participants in the Ca²⁺ entry mechanism in excitable cells, including neurons, different types of muscle cells and some endocrine cells. In contrast, the main pathway for the Ca²⁺ influx in non-excitable cells such as epithelial cells from most carcinomas is performed by SOCCs ( Figure 1 ). These channels generate the store-operated calcium entry (SOCE), originally called capacitative calcium entry. SOCCs open when ER Ca²⁺ stores are decreased from resting levels around 700 µM to about 200 µM (Alvarez and Montero, 2002; Villalobos et al., 2017). This partial depletion is sensed by the ER membrane-located Stromal Interaction Molecule 1 (STIM1) (Liou et al., 2005), when Ca²⁺ ions dissociate from its low affinity EF-Ca²⁺ binding domain. The decrease in ER-Ca²⁺ levels promotes STIM1 oligomerization and the interaction with the PM-localized calcium channel ORAI1 and/or TRP channels (Feske et al., 2006; Fahrner et al., 2017; Hernández-Morales et al., 2017; Secondo et al., 2018). The STIM1–ORAI1 interaction opens calcium release activated channels (CRAC), thus facilitating the calcium influx and the ER Ca²⁺-stores refilling for subsequent stimuli (Villalobos et al., 2017). In mammals, ORAI1 channel has two other isoforms, ORAI2 and ORAI3 encoded by homologous genes (Feske et al., 2006) and STIM1 only one STIM2 (Putney, 2018). In addition, there are two variants of ORAI1, the longer ORAI1α and the shorter ORAI1β, due to different translation points, with different membrane diffusion coefficients (Fukushima et al., 2012). The three ORAI isoforms can be activated by STIM1 with some variations in the pharmacology and biophysical properties of the channel (Lis et al., 2007; DeHaven et al., 2008).

Ca²⁺ release mechanisms in the ER are mediated by two major Ca²⁺ permeable channels: (1) ryanodine receptors (RyRs) (Fleischer et al., 1985) and (2) inositol trisphosphate (IP₃) receptors (IP₃Rs) (Berridge, 1983; Streb et al., 1983) ( Figure 1 ). RyRs open mainly when intracellular Ca²⁺ rises, thus acting as a ligand in a mechanism called, Ca²⁺-induced Ca²⁺ release (CICR) (Endo et al., 1970). ER-Ca²⁺ release by IP₃Rs starts at the PM, where agonist-induced G-protein-coupled receptors (GPCRs) activates the phospholipase C (PLC) enzyme. The PLC selectively induces the hydrolysis of the phosphatidylinositol 4,5-bisphosphate (PIP2), releasing diacylglycerol (DAG) and the second messenger IP₃, which diffuses to the ER activating its receptor (Berridge, 1987).

In mitochondria, the principal calcium channel is the mitochondrial calcium uniporter (MCU), a Ca²⁺-activated, calcium channel, whose molecular machinery has been recently reported (Perocchi et al., 2010; Baughman et al., 2011; Sancak et al., 2013). MCU opens when large [Ca²⁺] microdomains develop at the mouth of this Ca²⁺-operated, calcium channel. The huge mitochondrial potential (ΔΨ), close to −180 mV, promotes the Ca²⁺ removal from cytosol into mitochondria (Valero et al., 2008; Villalobos et al., 2017), clearing large cytosolic Ca²⁺ loads formed during VGCCs opening in excitable cells (Villalobos et al., 2001) or during Ca²⁺ release from the ER (Rizzuto et al., 1998). In various cellular types, SOCE regulation by mitochondria depends on the Ca²⁺ buffering capability of these organelles, being able to prevent the slow, Ca²⁺-dependent inactivation of Ca²⁺ release activated calcium channels (CRAC) (Gilabert, 2000; Hernández-Morales et al., 2017).

Intracellular Ca²⁺ concentrations control many different physiological and cellular functions at global and local levels, such as gene transcription in the nucleus, cell respiration and ATP synthesis in mitochondria or exocytosis in plasma membrane. To regulate this wide range of physiological Ca²⁺-dependent processes, the cells maintain Ca²⁺ concentrations tightly controlled. This regulation is known as calcium homeostasis.

To keep calcium homeostasis and considering that Ca²⁺ is a cation and does not cross freely cell membranes, Ca²⁺ is transported through PM and internal membranes by particular transmembrane proteins, including Ca²⁺ permeable channels, Ca²⁺ pumps and ion transporters (Bong and Monteith, 2018; Villalobos et al., 2018). As we mentioned above, Ca²⁺ permeable channels enable Ca²⁺ entry into cells forced by the electrochemical gradient, formed by the difference in Ca²⁺ concentration between the internal (100 nM) and extracellular (1 mM) space and the membrane potential of about −60 mV. The calcium entry rises intracellular [Ca²⁺] triggering different cell process. Then, it is removed from the cytosol and transported back to the extracellular medium or uptake into the intracellular Ca²⁺ stores by Ca²⁺ pumps and transporters, restoring the basal Ca²⁺ levels (Villalobos et al., 2018) ( Figure 1 ).

This removing-Ca²⁺ process requires energy provided by the ATP hydrolysis for Ca²⁺-pumps or the energy stored in the electrochemical gradient of other cation for transporters. For example, the Na⁺/Ca²⁺ exchanger transports three Na⁺ ions down its gradient in exchange of one Ca²⁺ cation against its electrochemical gradient (Reuter and Seitz, 1968). These dynamic Ca²⁺ signals differ with regard to their mechanisms of generation, spatial distributions and temporal properties, but are coordinated in space and time for a specific purpose. These calcium signals are characterized in different cell types and include calcium waves (Berridge et al., 2003; Parkash and Asotra, 2010), sparks (Cheng et al., 1993), calcium puffs (Yao et al., 1995), spikes (Meyer and Stryer, 1991), flickers (Wei et al., 2009), sparklets (Wang et al., 2001; Navedo et al., 2005; Tajada et al., 2017), etc. Compelling evidence show that variations in cellular Ca²⁺ dynamics participate in the normal and pathological signal transduction that controls cell proliferation and survival (Prevarskaya et al., 2018). Abnormal remodeling in Ca²⁺ homeostasis leads to the disruption of Ca²⁺ signaling resulting in a wide range of pathological conditions such as cell migration, excessive proliferation, invasion and programmed cell death resistance (Prevarskaya et al., 2011; Monteith et al., 2012; Prevarskaya et al., 2014).

Intracellular Ca²⁺-storage organelles like the ER, mitochondria and the recently emerged as a major intracellular Ca²⁺ storage, lysosomes (Lloyd-Evans and Waller-Evans, 2019), also hold their own Ca²⁺ transporters. The ER is the largest single organelle and the most important intracellular Ca²⁺ store (Lam and Galione, 2013). It operates as a dynamic Ca²⁺ store thanks to the combined action of Ca²⁺ channels and transporters in the ER-membrane, and the Ca²⁺-binding proteins in the ER-lumen, working as a high-capacity Ca²⁺ buffering system (Verkhratsky, 2005). Ca²⁺ is continuously leaking from the ER through leak channels still not identified. Nevertheless, Ca²⁺ concentration within the ER remains high due to the continuous activity of the endoplasmic reticulum Ca²⁺-ATPases (SERCA) that replenish Ca²⁺ stores (MacLennan, 1970) ( Figure 1 ). On the other hand, activation of the IP₃Rs, receptor-operated Ca²⁺ channels, release Ca²⁺ from intracellular store sites, contributing to the maintenance of a total amount of Ca²⁺ in the lumen similar to the extracellular space, in the mM range (Alvarez and Montero, 2002; Foskett et al., 2007). Because the lumen contains high concentrations of Ca⁺² binding proteins (calreticulin, calsequestrin, annexin, calnexin, etc.) the concentration of free Ca⁺² has been estimated to be between 100 and 700 µM (Foskett et al., 2007; Yáñez et al., 2012).

In the mitochondria, the Ca²⁺ uptake is conducted by the MCU and the Na⁺/Ca²⁺ (NCLX) and Ca²⁺/H⁺ (HCX) exchangers are responsible for the mitochondrial Ca²⁺ release in exchange for Na⁺ and H⁺, respectively (Bononi et al., 2012; Srinivasan et al., 2015) ( Figure 1 ). A large increase in Ca²⁺, located near enough the MCU, triggers the influx of calcium to the mitochondrial matrix, rising the mitochondrial [Ca²⁺] to very high concentrations near the mM level (Pozzan et al., 2000; Contreras et al., 2010). Mitochondria are also in dynamic contact with other organelles including the ER. These transient contacts between ER and mitochondria are essential to generate the highly localized and concentrated Ca²⁺ microdomains, facilitating the Ca²⁺ transport into mitochondria (Paupe and Prudent, 2018). Through this mitochondrial-ER crosstalk, IP₃Rs control the mitochondrial Ca²⁺ uptake and therefore metabolism and cell destiny (Cui et al., 2017). Although the mitochondria play an important role in Ca²⁺ homeostasis, the “in vivo” buffering capacity of this intracellular organelle is not particularly relevant (Pozzan et al., 2000).

Mitochondria not only modulate cytosolic Ca²⁺ signal. Mitochondrial calcium is also involved in the control of metabolism, ATP production and the regulation of cell death. Mitochondrial calcium regulates three important enzymes of the Krebs cycle: ketoglutarate, isocitrate, and pyruvate dehydrogenase. The effect of mitochondrial Ca²⁺ accumulation in Krebs cycle is the increase in the respiration rate and ATP synthesis (Mammucari et al., 2018). On the other hand, an excess of mitochondrial Ca²⁺ uptake, known as “mitochondrial calcium overload” triggers mitochondrial permeability transition pore (mPTP) opening. This is a high-conductance channel mediating mitochondrial swelling (Petronilli et al., 1993). This, together with other factors, triggers mitochondrial permeability transition, disruption of the mitochondrial potential and a massive release of cytochrome c, leading to the apoptosome activation and apoptosis (Giorgi et al., 2012; Mammucari et al., 2018).

The plasmalemma also displays many different calcium channels, ATP pumps and transporters to maintain the intracellular Ca²⁺ homeostasis. We have mentioned above the channels responsible of the Ca²⁺ influx. Now we will briefly describe the players involved in the transport of calcium out of the cell to maintain the Ca²⁺ electrochemical gradient. Two players in the Ca²⁺ outflow from cells have been described, the Na⁺/Ca²⁺ exchange transporter (NCX) and the plasma membrane Ca²⁺-ATPase (PMCA) ( Figure 1 ). The NCX is in charge of Ca²⁺ extrusion from the cytoplasm against its electrochemical gradient without ATP consumption, in fact, the electrochemical gradient of sodium stores that energy. In addition, NCX can operate in reverse mode contributing to Ca²⁺ entry in different conditions, such as cellular activation (Blaustein and Lederer, 1999). The PMCA pump with a 1:1 Ca²⁺/ATP stoichiometry possesses a high-affinity but a low-capacity for Ca²⁺ transport, in total opposition to NCX (Noble and Herchuelz, 2007). This characteristic has conditioned the roles of these Ca²⁺ transporters. The PMCA performs a housekeeping role maintaining cytosolic Ca²⁺ around its basal level, whereas the NCX eliminates significant rises in intracellular Ca²⁺, but this model has been revised during the latest years. See (Brini and Carafoli, 2011) for review.

Overwhelming evidence provided in the last decades strongly suggest that acetylsalicylic acid (ASA), or aspirin provide protection against several forms of cancer, particularly those in the gastrointestinal tract (Chan et al., 2012; Rothwell et al., 2012; Drew et al., 2016). Same evidence has been also provided for a series of non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, flurbiprofen and sulindac, either alone or, in combination with other compounds like difluoromethylornithin (DFMO), a suicide inhibitor of polyamine biosynthesis (Tegeder et al., 2001; Rostom et al., 2007; Meyskens et al., 2008; Thompson et al., 2010; Chan et al., 2012; Dolejs et al., 2016). Evidence includes multiple data in cell lines and model animals, but also tens of epidemiological studies. Aspirin and NSAIDs inhibit several characteristic cancer cell hallmarks, including unrestrained cell proliferation, cell migration and invasion and cell death resistance. Numerous series of epidemiological evidences suggested that regular use of aspirin and/or several NSAIDs provide significant reduction in the risk of developing several forms of cancer and, particularly colorectal cancer. However, recommendation to use these over the counter drugs for cancer chemoprevention is hindered by the well-known secondary effects and/or risks of the regular use of NSAIDs leading to the conclusion that if, for any other reason or condition, individuals use NSAIDs regularly, they are probably protected against several forms of cancer. For any other situation, recommendation remains at hands of Doctors, that must evaluate whether the risk of taking NSAIDs is worthy in some cases of high risk of cancer. In fact, several studies have concluded that individuals at high risk of developing some forms of hereditary cancer like Lynch Syndrome may benefit of taking aspirin and/or NSAIDs to help protecting them from cancer (Burn et al., 2011; Yurgelun and Hampel, 2018). This may also apply to those patients that have received surgery for removing of polyps and/or tumors in the gastrointestinal tract that are also at high risk of recurrence. In these particular cases, the benefits are supported by several clinical trials that have addressed specifically the treatment and dose. For example, a clinical trial based in the combination of sulindac with DFMO in patients with previous tumors indicate that this combination may reduce nearly 90% the risk of developing recurrences (Meyskens et al., 2008; Sporn and Hong, 2008), revised in (Laukaitis and Gerner, 2011).

The action mechanisms of these drugs involved in preventing cancer cell hallmarks and cancer itself have been addressed in a large series of studies but they remain obscure. Most studies have addressed the contribution of inflammation to carcinogenesis (Balkwill and Mantovani, 2001; Coussens and Werb, 2002) and the benefits of inhibiting inflammatory mechanisms in cancer cell (Hudes et al., 2013; Wu et al., 2013). However, although inflammation definitely contributes to cancer risk, several evidences suggest that additional and/or alternative mechanisms may contribute as well and some relevant mechanisms include modulation of the expression and/or activity of calcium permeable channels in cancer cells (Déliot and Constantin, 2015; Hoth, 2016; Prevarskaya et al., 2018).

Núñez et al. (2006) reported that salicylic acid, the most important metabolite of aspirin, inhibited store-operated Ca²⁺ entry (SOCE) and SOCE-dependent cell proliferation in colon cancer cells (Núñez et al., 2006; Valero et al., 2008). This effect cannot be attributed to inhibition of cyclooxygenase (COX) as salicylic acid lacks the acetyl moiety involved in COX acetylation, the mechanism involved in COX inhibition by aspirin. Also, it is achieved at concentrations far lower than the necessary to inhibit COX expression. Finally, the effects are similar in cells lacking COX2 expression implying that an alternative target is involved. On the other hand, same results are obtained by other NSAIDs including ibuprofen, indomethacin, sulindac and R-flubiprofen, the enantiomer unable to inhibit COX activity. Accordingly, salicylate and other NSAIDs inhibit SOCE and cell proliferation independently of COX activity and/or gene expression. Since SOCE is critical for cell proliferation, these drugs inhibit cell proliferation more likely because they inhibit SOCE rather than inflammatory pathways. This paradoxical view could be reconciled taken into account that SOCE may also contribute to inflammatory pathways as it is key in the activation of all cell types, including inflammatory cells. Importantly, inhibition of cell proliferation by salicylic acid is counteracted simply by enhancing extracellular Ca²⁺ just to restore Ca²⁺ entry in colon cancer cells. When taken together, these data indicate that salicylate (aspirin) and NSAIDs prevent cell proliferation in tumor and non-tumoral cells by inhibiting SOCE in a COX-independent manner.

In search for the mechanism of inhibition of SOCE by salicylate and other NSAIDs, Villalobos and cols. tested the effects of these drugs directly on Ca²⁺-release activated currents (CRAC) responsible for SOCE in rat basophilic leukemia cells (RBL) and other cell types (Muñoz et al., 2011). These currents display a strong Ca²⁺-dependent inactivation (Hoth et al., 1997; Fierro and Parekh, 2000) that render them unable to operate in a few seconds unless nearby mitochondria take up this calcium and sustain the current. In this sense, CRAC channels are dictated not only by the filling state of intracellular Ca²⁺ stores but also by mitochondria (Villalobos et al., 2018). Inhibition of the MCU, the calcium channel responsible of mitochondrial Ca²⁺ uptake, with ruthenium salts derivatives like RU386 or mitochondrial uncouplers like FCCP, that collapse the mitochondrial potential, the driving force for mitochondrial Ca²⁺ uptake, inhibit mitochondrial ability to take up Ca²⁺, thus leading to Ca²⁺-dependent inactivation of CRAC channels (Villalobos et al., 2019). Similar results have been obtained by MCU downregulation (Samanta et al., 2019). Salicylate and other NSAIDs are carboxylic acids bound to aromatic rings, the typical chemical structure of mitochondrial uncouplers. Accordingly, these drugs are able to decrease the mitochondrial potential or even collapsing it depending on concentration (Muñoz et al., 2011; Scatena, 2012; Hernández-Morales et al., 2017). As a consequence, at low concentrations they work as mild mitochondrial uncouplers that prevent mitochondrial Ca²⁺ uptake, leading to the Ca²⁺-dependent inactivation of CRAC channels and SOCE inhibition in RBL cells. In conditions of high intracellular concentration of the Ca²⁺ buffer, when the Ca²⁺-dependent inactivation cannot be achieved regardless of mitochondria, neither salicylate, NSAIDs nor MCU removal promote CRAC inactivation or SOCE inhibition. Therefore, salicylate and selected NSAIDs do not inhibit CRAC channels directly. Instead, these drugs promote the Ca²⁺-dependent inactivation of these channels by preventing the Ca²⁺ uptake by mitochondria exactly as if we remove the MCU (Villalobos et al., 2019). These same results have been obtained also in other cell types as well, including vascular smooth muscle cells (VSMCs) (Muñoz et al., 2011; Muñoz et al., 2013) and colonic cells both normal and tumoral (Hernández-Morales et al., 2017).

Interestingly, the effects of salicylate and NSAIDs are achieved at very low concentrations in normal VSMCs leading to a full arrest of cell proliferation. VSMCs undergo phenotypic remodeling in different physiopathological situations. For example, upon damage, VSMCs may transform from differentiated, contractile cells to a proliferative and migrating phenotype that restores injury and returns to the differentiated phenotype. This process helps restoring damaged vessels but it may not be as beneficial if excessive proliferation occludes vessels as it happens in restenosis. This transdifferentation process is mediated by a change in the prevalence of different Ca²⁺-permeable channels. In the differentiated phenotype, voltage-gated channels sensitive to dihydropyridines are prevalent. However, in the proliferative state, store-operated Ca²⁺ channels take the lead. These channels show strong Ca²⁺-dependent inactivation that is prevented by mitochondria. Accordingly, low concentrations of salicylate and NSAIDs inhibit SOCE and cell proliferation in these cells during the proliferative phenotype but have no effect on Ca²⁺ entry during the differentiated phenotype. In fact, they have been proposed for treatment of restenosis, or excessive VSMC proliferation after stent implantation in coronary arteries (Weber et al., 2000; Koo et al., 2007; Dannoura et al., 2014).

As stated above, sensitivity of store-operated channels to aspirin and NSAIDs depends on mitochondria. As mitochondria from normal and tumor cells differ because of the Warburg effect, perhaps mitochondrial control of store-operated channels may be different as well in normal and colon cancer cells. Hernández-Morales et al. (2017) reported recently that this is indeed the case, at least in normal and colon cancer cells. Mitochondria from normal cells are not powerful enough to remove completely the Ca²⁺-dependent inactivation of store-operated channels. However, in cancer cells, probably because of the Warburg effect, mitochondria display enhanced mitochondrial potential and remove efficiently Ca²⁺, thus preventing efficiently the Ca²⁺-dependent inactivation of store-operated channels and sustaining Ca²⁺ entry (Hernández-Morales et al., 2017). Supporting this idea, the RNA expression analysis of genes involved in mitochondrial Ca²⁺ transport indicate that, MCU positive-modulator genes are overexpressed while negative-modulators are underexpressed in colon cancer cells (Pérez-Riesgo et al., 2017).

As stated above in the review, another difference between normal and colon cancer cells is that SOCE in normal colonic cells involves only ORAI1-mediated CRAC channels. In contrast, in colon cancer cells, SOCE is mediated by both ORAI1 and TRPC1 channels. Whereas ORAI1 channels in normal cells are essentially inactivating, in colon cancer cells, perhaps the involvement of TRPC1 channels may contribute to sustain currents. A possibility recently pointed out is that Na⁺ influx mediated by TRPC1 channels may favor activity of the mitochondrial Na⁺/Ca²⁺ exchanger, in turn preventing mitochondrial Ca²⁺ overload and the ensuing formation of reactive oxygen species (ROS) and ROS-dependent inactivation of ORAI1 channels (Quintana et al., 2011; Villalobos et al., 2018). This form of ROS-dependent regulation of ORAI1 channels remains controversial (Samanta et al., 2018; Samanta et al., 2019; Parekh, 2019).

In addition to aspirin and NSAIDs, other drugs have been reported to provide chemoprotection against several forms of cancer, particularly colorectal cancer. The most critical compound is DFMO, also called eflornithine. DFMO is considered a suicide inhibitor of ornithine decarboxylase 1 (ODC1), the critical enzyme in the biosynthesis pathway of the main mammalian polyamines: putrescine, spermine and spermidine. This enzyme is usually overexpressed in cancer cells, thus explaining the increased levels of polyamines that may contribute to cancer cell hallmarks, including enhanced cell proliferation, migration and invasion (Luk and Baylin, 1984; Pegg, 1988; Giardiello et al., 1997; Weiss et al., 2002). Several authors have reported ODC1 polymorphisms and robust correlation between specific polyamines and tissue growth (Martínez et al., 2003; Pegg, 2016; Wang et al., 2017; Sánchez-Jiménez et al., 2019). Finally, different growth stimuli including tumor promoters are able to enhance ODC activity and tumor formation (Bachmann and Geerts, 2018; Gerner et al., 2018). These effects are inhibited by DFMO, including inhibition of colon carcinogenesis in cancer models, such as the ApcMin/+ mice with high ODC levels and polyamines in the gastrointestinal tract. Interestingly, combinations of DFMO and NSAIDs have synergistic effects and inhibit dramatically carcinogenesis in both the small and large intestines of these mice. Recent clinical trials indicate that DFMO prevents CRC, especially if combined with sulindac, a carboxylic NSAID (Meyskens et al., 2008; Thompson et al., 2010; Burke et al., 2016).

Recent data reported by Gutierrez et al., suggest that DFMO may inhibit carcinogenesis by partially reversing the remodeling of store-operated Ca²⁺ channels in colorectal cancer cells (Gutiérrez et al., 2019). As stated above, colorectal cancers undergo a remodeling of intracellular Ca²⁺ homeostasis consisting in enhanced store-operated Ca²⁺ entry and decreased Ca²⁺ store content that contributed to cancer cell hallmarks, including enhanced cell proliferation, invasion and survival (Sobradillo et al., 2014; Villalobos et al., 2016; Villalobos et al., 2017). Villalobos and cols. have proposed that, during carcinogenesis, colorectal cancer cells may switch from a small, transient SOCE based on ORAI1-dependent CRAC channels (normal cells) to large and sustained currents depending on both ORAI1 and TRPC1 channels (tumor cells) (Villalobos et al., 2016; Villalobos et al., 2017; Villalobos et al., 2019). Interestingly, DFMO treatment inhibits cancer cell hallmarks in these cells including cell proliferation and cell death resistance. These effects are associated to SOCE inhibition and enhancement of Ca²⁺ store content. Therefore, DFMO may inhibit cancer cell hallmarks by reversing Ca²⁺ remodeling in colorectal cancer cells (Gutiérrez et al., 2019). Further research revealed that DFMO treatment inhibits TRPC1 expression and eliminates the TRPC1 component of the store-operated currents in colon cancer cells. These effects are reversed in the presence of polyamine putrescine (Gutiérrez et al., 2019). Collectively, these data suggest that polyamines promote Ca²⁺ channel remodeling by inducing expression of TRPC1 channels and this change promotes cancer cell hallmarks. In fact, this process may simply represent the exacerbation of the physiological process known as epithelial restitution that is mediated by transient polyamine synthesis induce by epithelial damage (Rao et al., 2012). While in physiological conditions this is a transient process limited by the repair of the wound epithelium, in cancer cells this process may became chronic due to ODC overexpression associated to activation of c-myc oncogene secondary to mutations in APC.

As stated above, combination of DFMO plus sulindac prevents efficiently colorectal cancer in high risk patients. An ongoing, large scale, three phase clinical trial is presently testing this treatment for patients at high risk of CRC (S0820, Adenoma and Second Primary Prevention Trial—Full Text View—ClinicalTrials.gov). Interestingly, Gutierrez et al. have reported that the combination of DFMO plus sulindac removes not only the TRPC1 component of the store-operated currents but also the ORAI1-dependent, thus fully abolishing the current. The mechanisms are different. The TRPC1-dependent current is removed at the expression level. However, the ORAI1-dependent current is simply inactivated because the mitochondria-dependent potentiation of the current is prevented. In summary, these data suggest a critical role for Ca²⁺ channel remodeling in cancer and provide a molecular mechanism of cancer chemoprevention targeting the remodeling of ion channels.

It is clearly evident in the literature, that Ca²⁺-permeable channels, transporters and pumps play important roles in a wide range of cancer-related process. The remodeling of these Ca²⁺-permeable channels contributes to the Ca²⁺-homeostasis dysregulation and both regulate several of the well-known cancer hallmarks. The influence of Ca²⁺ and other ion channels in carcinogenesis is so evident, that cancer was recently described as a channelopathy. This is a relative new field, however important advances in the identification of mechanism relating ion channels and cancer has been done. For this reason, ion channels represent a novel and possibly important clinical targets for some cancer types, with only a few channel blockers tested in clinical trials.

The use of ion channels modulators as chemotherapeutic agents has their pros and cons. Most of the Ca²⁺-permeable channels are ubiquitously expressed in different tissues, playing an important role in normal cell function. This is why, the pharmacological modulation of a specific cancer-related channel in tumor cells may produce significant toxicity in normal cells. Further research is required to take full advantage of channel modulators for cancer prevention, diagnosis and treatment.

Both authors contributed equally to the writing of the manuscript.

This work has been supported by competitive grants RTI2018-099298-B-100 from Ministerio de Ciencia, Innovación y Universidades, Spain, BFU2015-70131 from Ministerio de Economía y Competitividad, Spain and VA294P18 from Junta de Castilla y León, Spain.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.