The Role of Calcium in Actin-Dependent Cell Migration and Invasion in Cancer

Abstract

Calcium is an essential signaling molecule that plays a crucial role in regulating various cellular processes, including actin cytoskeleton dynamics and cell migration. In this chapter, we will explore the advances in our understanding of how calcium signaling influences the dynamics of actin cytoskeleton, and how dysregulation of calcium signaling can contribute to tumor progression and metastasis. We will discuss the mechanisms by which calcium regulates these processes and the potential implications for cancer diagnosis and treatment. Additionally, we will examine the role of calcium-dependent signaling molecules such as calmodulin, calcium-activated protein kinases, and calcium channels in regulating actin dynamics. Finally, we will highlight emerging research on the use of calcium channel blockers as a potential therapeutic approach for cancer treatment.

1. Introduction

Calcium, a ubiquitous second messenger, is fundamental to a variety of cellular functions [1, 2]. It has significant roles in muscle contraction, cell division, gene expression, cell migration, and even programmed cell death. The intricate signaling of calcium is initiated either by its release from intracellular stores or by influx from the external environment. This rise in the concentration of calcium within the cell sets off a cascade of downstream reactions, eventually leading to desired cellular responses. The subsequent processes can take various forms, such as the activation of protein kinases, modulation of gene expression by transcription factors, or the regulation of diverse cell behaviors like cell division and migration. In essence, calcium signaling serves as a complex and adaptable network that regulates a broad range of cellular activities.

Alongside calcium, the actin cytoskeleton, comprised of microfilaments and actin bundles, is a vital component of cellular mechanics. It underpins cell structure, provides the machinery for cellular movement, and assists in cell adhesion [3]. Its role in anchoring cells to the extracellular matrix (ECM) is critical for cell migration, as it enables effective navigation across the ECM [4]. Moreover, the actin cytoskeleton is instrumental in cell division, as it aids in the organization of key components and facilitates chromosome separation. Importantly, the actin cytoskeleton is in a state of constant flux. It can swiftly respond to changes in the environment by adjusting the balance between actin polymerization and depolymerization, thereby changing the shape of cells and movement.

Alterations in calcium signaling pathways have been linked to various diseases, including cancer [5]. Dysregulation in calcium signaling can foster tumor growth, metastasis, and resistance to cell death. Several calcium channels and pumps contribute to the growth and proliferation of cancer cells and play a significant role in modulating cytoskeletal dynamics and cell motility—key factors in the metastasis process. Furthermore, calcium signaling is connected to the epithelial-mesenchymal transition (EMT), a biological procedure intimately involved in cancer metastasis. Disruptions in these pathways have been observed in a wide range of cancers, including breast, colorectal, prostate, and pancreatic cancer. This highlights the fundamental role of calcium signaling in cancer progression and underlines the potential therapeutic value of targeting these pathways.

Given the complex interplay between calcium signaling and actin dynamics, this relationship becomes crucial in the context of cancer, where cell migration and invasion are pivotal to cancer progression and metastasis. Understanding this interplay can shed light on the mechanisms propelling cancer progression. Insights from these studies offer promising avenues for developing therapeutic interventions targeting these intricate cellular mechanisms. Therefore, the aim of this review is to elaborate on the current understanding of how calcium signaling influences actin dynamics in cells, explore the underlying molecular mechanism, and discuss the potential therapeutic strategies arising from these insights. The review is structured as follows: we begin by discussing the fundamental roles of calcium signaling and the actin cytoskeleton in cell function, then delve into the evidence linking disruptions in calcium signaling to various forms of cancer. Finally, we explore the potential therapeutic strategies that target calcium signaling pathways and actin dynamics to curb cancer progression and metastasis.

2. Shaping the actin cytoskeleton: the role of calcium signaling

Actin, a protein present ubiquitously across all eukaryotic cells, exists in a globular form, playing a crucial role in the formation of microfilaments—fine, threadlike structures that undergird cellular structure. These microfilaments not only contribute to the structural integrity of cells but are also critical for various cellular functions such as motility and intracellular trafficking. The actin cytoskeleton is characterized by its dynamic reshaping through a fascinating cyclical process of polymerization and depolymerization. Polymerization involves the assembly of individual actin monomers, or G-actin, into filamentous structures, known as F-actin, a process powered by ATP binding and hydrolysis. Conversely, depolymerization is the reverse process where F-actin disintegrates back into G-actin monomers. This transition between these states is precisely regulated by numerous factors, such as ATP hydrolysis and the binding of specific proteins, which cap filament ends or sever them to control assembly.

These dynamic cycles of polymerization and depolymerization enable the actin cytoskeleton to rapidly reorganize, allowing it to adapt responsively to cellular needs. Intracellular calcium signaling plays an essential role in maintaining this equilibrium between G-actin and F-actin, underscoring its importance in cellular health and functionality. Calcium signaling operates at the intersection of two primary cellular systems: intracellular signaling and cytoskeletal dynamics. The complexity of calcium’s role stems from its ability to influence the actin cytoskeleton both directly, via its interaction with actin or actin-binding proteins (ABPs) [6, 7], and indirectly, through its regulation of protein kinases and other signaling proteins that modify the actin cytoskeleton. In turn, actin cytoskeleton can also modulate the calcium channel activity.

Calcium signaling [2, 8], a crucial cellular process involving the transmission of signals through the ion Ca²⁺, plays a significant role in regulating the dynamics of the actin cytoskeleton [9, 10]. Calcium ions play a crucial role as an intracellular signal in regulating various cellular processes. It operates over a wide temporal range and exhibits versatility in its functions [1]. The intracellular signaling systems involving Calcium utilize an extensive toolkit to assemble signaling pathways with diverse spatial and temporal dynamics. One important aspect of calcium signaling is the generation of rapid and highly localized calcium spikes [11]. These spikes are responsible for regulating fast cellular responses. They occur in specific regions of the cell and are tightly controlled to ensure precise signaling. On the other hand, slower cellular responses are controlled by repetitive global calcium transients or intracellular calcium waves. These transients and waves involve the propagation of calcium signals throughout the cell, allowing for the coordination of various cellular processes [12]. Furthermore, calcium not only acts as a signaling molecule but also directly influences the expression patterns of its own signaling systems. The expression of calcium signaling components is constantly being remodeled in both healthy and diseased states. This remodeling is essential for maintaining cellular homeostasis and adapting to changing conditions, in particular, during cell migration where an established gradient of calcium concentration ranging from lower at the cell forefront to higher at the rear plays a crucial role. The slightest variations in this low background calcium level at the front can effectively relay signals, prompting activities such as local lamellipodia retraction and adhesion [13, 14]. Tissue damage induces a calcium cascade that sparks significant actin cytoskeleton modifications for wound healing like the formation of contractile rings and membrane protrusions at the wound margins [15]. Yet, the detailed mechanisms linking calcium signaling to these changes in cell morphology and behavior are not fully understood.

It is important to recognize the mechanisms that regulate intracellular calcium levels, and the main regulatory mechanisms can be broadly categorized into five groups: voltage-gated calcium channels (VGCCs) [16]; transient receptor potential (TRP) [17]; receptor-operated calcium channels (ROCCs); store-operated calcium channels (SOCCs) [18]; ryanodine receptors (RyR) [19]; the IP3/DAG pathway [20]. Each of these groups functions in distinct ways. For example, VGCCs open in response to plasma membrane depolarization, allowing the influx of calcium from the extracellular space. On the other hand, ROCCs open upon binding of signal molecules to cell surface receptors. SOCCs are activated when the endoplasmic reticulum’s calcium stores are depleted, a process often associated with the STIM/ORAI pathway, where STIM1 proteins in the endoplasmic reticulum sense low calcium levels and activate ORAI proteins in the plasma membrane, leading to store-operated calcium entry (SOCE). In the case of the IP3/DAG pathway, phospholipase C (PLC) gets activated by cell surface receptors and proceeds to convert phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). The binding of IP3 to IP3Rs triggers the opening of calcium channels, leading to the release of calcium ions from the ER into the cytoplasm. Meanwhile, RyRs are calcium-sensitive channels located in the endoplasmic reticulum membrane that can release calcium in response to an initial small calcium influx, a process known as calcium-induced calcium release.

2.1 Calcium signaling: directing the dynamics of the actin cytoskeleton

The interplay between calcium signaling pathways and the regulation of actin cytoskeleton has garnered substantial interest from the research community. C, for instance, serves a regulatory function in the activity of profilin, an ABP that promotes actin polymerization through catalyzing the exchange of ADP for ATP [21]. An increase in calcium concentration results in the sequestration of the profilin-G-actin complex, which in turn inhibits actin polymerization [22].

In the same context, gelsolin [23], an actin binding protein that manipulates actin dynamics, demonstrates an interesting interplay with calcium. Gelsolin was initially recognized due to its unique ability to change macrophage extracts from a viscous, gel-like consistency to a more fluid state. This characterization was subsequently linked to response to calcium, particularly its ability to sever F-actin [24]. Gelsolin is more than a simple actin-severing protein; it is a multifaceted regulator of actin dynamics, capable of not just cleaving actin filaments, but also capping them, trapping actin monomers, and even facilitating the formation of actin filaments. The functionality of gelsolin, like profilin, is also closely regulated by calcium binding, emphasizing the pivotal role of calcium in the regulation of proteins involved in actin dynamics.

Another key aspect of the interaction of calcium with ABPs involves Caldesmon that binds to actin filament and inhibits the interaction of actin-myosin ATPase activity. This inhibition prevents smooth muscle cells from contracting and therefore modulates actin dynamics [25, 26, 27].

Prominent among the calcium-regulated ABPs are EF-hand containing proteins such as EFHD/Swiprosin have been implicated in the regulation of actin cytoskeleton dynamics and calcium signaling [28]. It has been shown that EFhD2/Swip-1, regulated by calcium levels, plays an instrumental role in driving cell migration and wound healing. The study showed shows that transient calcium spikes modulate the cross-linking activity of EFhD2/Swip-1 with actin filaments, triggering a quick reorganization of the actin cytoskeleton. This rapid rearrangement plays a crucial role in promoting wound closure. This data underlines the intricate relationship between calcium signaling and the dynamics of actin cytoskeleton reorganization. Recent studies provide evidence for the role of calcium fluxes in relaying information to the actin cytoskeleton and identifies EFhD2/Swip-1 as a calcium-dependent actin cross-linking protein involved in lamellipodial cell migration and wound closure [29].

Calcium ions (Ca²⁺) play a pivotal role in indirectly regulating actin dynamics by activating calcium-binding proteins. Notably, calmodulin (CaM) and Protein Kinase C (PKC) are significantly involved in these processes. In the presence of calcium ions, calmodulin, a ubiquitous and versatile mediator of calcium signaling, undergoes conformational changes [30]. Enabling it to interact with and activate various downstream targets, one of which is Myosin Light Chain Kinase (MLCK) [31, 32]. This activation enables myosin light chain to interact with actin filaments, creating contractions and facilitating cell movement, and cell shape changes [2].

Calcium additionally impacts the function of another ABP, cofilin, which plays a key role in regulating actin filament dynamics and depolymerization [33]. Cofilin typically becomes deactivated when phosphorylated, but it can be reactivated by dephosphorylation through the phosphatase Slingshot, a process that gets triggered by an increase in intracellular calcium levels [34]. Slingshot, a ubiquitous serine/threonine protein phosphatase, is regulated by calcineurin, which is another downstream target of calmodulin. Thus, intracellular calcium elevation leads to calcineurin activation and subsequent cofilin activation. This connection between calcium levels and cofilin activity highlights the pervasive influence of calcium ions on actin dynamics.

Alongside calmodulin, calcium-activated Protein Kinase C (PKC), a family member of serine/threonine kinases, significantly contributes to the modulation of actin dynamics. PKC phosphorylates a wide range of proteins, one of which is MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate) [35]. This phosphorylation event releases actin-bound PIP2 (phosphatidylinositol 4,5-bisphosphate), facilitating the generation of new actin branches, a key element in actin polymerization and cell migration [36, 37]. The creation of these new branches is a pivotal process in actin polymerization and cell migration.

Consequently, these complex interactions between calcium ions and proteins involved in actin dynamics underscore the vital role of calcium signaling in cell migration and potentially cancer progression.

2.2 Reciprocal influence: actin regulates calcium channels

The actin cytoskeleton also has an instrumental role in the regulation of calcium flux through its modulation of ion channels. This regulation arises from the direct interactions between actin filaments or ABPs and ion channels, including VGCCs, leading to alterations in their activity [28, 29, 38, 39, 40]. This interaction has been shown to have significant implications on cellular physiology as it influences calcium influx into cells, thereby affecting an array of cellular processes. Evidence for the regulation of calcium flux by the actin cytoskeleton spans various cell types and physiological conditions. For instance, in osteoblasts, disruption of the actin cytoskeleton has been linked with a negative shift in inactivation voltage and a decrease in peak current of L-type calcium channels [41]. Similarly, T-cells showed inhibited SOCCs upon actin cytoskeleton disruption [42]. Interestingly, actin dynamics in mast cells regulated by drebrin have been found to play a critical role in IgE-dependent mast cell activation and allergic responses, which are known to involve calcium signaling [43]. Moreover, the actin cytoskeleton’s influence extends to the endoplasmic reticulum, where it has been implicated in the regulation of calcium release [38].

Interestingly, the interaction between the actin cytoskeleton and its interaction with the KRas-induced actin-interacting protein controls calcium signaling via IP3 receptors (IP3Rs), with actin filaments providing an anchor for IP3Rs. This anchoring process significantly contributes to the initiation and enhancement of calcium signals, outlining the crucial role of the actin cytoskeleton and KRAP in governing the spatial distribution, strength, and timing of these calcium signals within the cell. A comprehensive study delved into the intricate modulation of T-type calcium currents by Kelch-like 1 (KLHL1), an ABP [44]. Their insightful investigation revealed a fascinating interplay between KLHL1, the polymerized actin cytoskeleton, and the pore-forming subunit of the CaV3.2 channel. This complex interaction notably boosts the number of active channels present at the plasma membrane, leading to an amplified up-regulation of T-type calcium currents. Further studies elucidated the role of the actin cytoskeleton in calcium channel regulation through their study on the interaction between actinin 4 and the β3 subunit of L-type calcium channels [39]. Within osteoblasts, they demonstrated that the actin cytoskeleton significantly modulates L-type calcium channel activity, with disruption of actin filaments having a direct impact on channel functionality. The role of the actin cytoskeleton extends beyond these specific interactions. Studies have explored the intriguing dialogue between L-type calcium channels and mitochondria, highlighting the critical role of actin in maintaining calcium homeostasis and deftly managing mitochondrial energetics within the heart [45].

The elucidation of the relationship between actin and calcium signaling in a variety of cell types also broadens our understanding of how cellular processes are intricately linked, reinforcing the notion that cell functions are interdependent and tightly controlled. Despite the wealth of knowledge accumulated thus far, the exact mechanisms by which actin filaments modulate ion channel activity and calcium flux remain under investigation.

3. Calcium channels and calcium signaling: key players in cancer development

In the field of cellular physiology, aberrations of calcium signaling pathways are increasingly recognized for their significant role in initiating and advancing various types of cancer [40, 46]. Given calcium’s fundamental role in many cellular processes, including proliferation and migration, any perturbations in calcium homeostasis can lead to significant shifts in cell behavior, potentially fostering an environment favorable for cancer development and progression. As such, the significance of calcium channels in these processes cannot be overstated. Indeed, recent studies have begun to shed light on the critical roles these channels play in tumorigenesis. In the following section, we will delve into the various calcium channels and mechanisms that are implicated in the dysregulation of calcium signaling and its impact on cancer cell migration and invasiveness. Studies found a strong correlation between high levels of serum ionized calcium and the severity of endometrial cancer, with TRPV4 playing a critical part. High TRPV4 expression is associated with cancer progression both in vitro and in vivo [47]. Through proteomic and bioinformatics analysis, the study reveals that TRPV4 regulates the cytoskeleton and the Rho protein pathway, which in turn influences EC cell migration. It further uncovers a mechanism where TRPV4 and calcium influx impact the cytoskeleton via the RhoA/ROCK1 pathway [48], leading to the activation of cofilin and affecting F-actin and paxillin levels. These findings underline the relevance of ionized serum calcium levels as an indicator of poor EC outcomes. Other TRP channels also contribute to the regulation of cell migration in cancer. TRPC1, TRPC3, and TRPV6 channels have been implicated in breast cancer cell migration and invasion [49]. Activation of TRPC1 results in increased intracellular calcium levels, leading to the activation of downstream effectors involved in migration such as Rho GTPases. On the other hand, TRPC3 has been shown to promote migration and invasion in breast cancer cells via the activation of Rac1, a small GTPase involved in actin cytoskeletal rearrangement [50]. Furthermore, TRPV6, a calcium-selective channel that is overexpressed in various cancers, including breast cancer, has been associated with enhanced migration and invasion.

Concurrently, there is a growing body of research investigating the role of other calcium channels in cancer development. For example, studies on the Orai3 calcium channel have demonstrated its implication in the regulation of breast cancer cell migration in calcium-dependent mechanisms. Notably, Orai3-mediated calcium entry promotes the remodeling of the actin cytoskeleton that involve downstream effectors such as calpain and focal adhesion kinase (FAK) [51]. The activation of calpain, a calcium-dependent protease, leads to the proteolysis of key actin cytoskeletal proteins, ultimately affecting cell adhesion dynamics and promoting cellular movement. Orai3 have also been shown to directly interact with FAK, a central regulator of cell migration to trigger signaling cascades that modulate the actin cytoskeleton and focal adhesion turnover, consequently influencing cell migration in breast cancer. Furthermore, With the advent of high throughput RNAi screening technology, stromal interaction molecule 1 (STIM1) and Orai1 have been identified as the ER Ca²⁺ sensor and the plasma membrane channel pore-forming unit of SOC channels, respectively [52]. Their crucial roles in cancer cell migration, invasion, and metastasis came to light in breast cancer research first reported in 2009. Since then, evidence has been mounting, pointing towards a significant function of SOC channels in tumor progression and metastasis. Presently, it’s increasingly recognized that the activation of SOCE is a common occurrence in diverse cancers, promoting cell motility, invasiveness, and metastatic progression. Overexpression of STIM and/or Orai proteins has been found to correlate with metastatic conditions and shorter survival spans in several cancers [53, 54]. Moreover, the perturbation of SOCE by employing either STIM1 and Orai1 shRNAs or pharmacological inhibitors, has proven significantly effective in curbing the mobility and invasiveness of breast cancer cells in vitro [55]. The profound effect of this intervention extends to the halting of lung metastasis in mouse models [55]. In a remarkable twist, however, the deliberate intensification of SOCE through the exogenous expression of STIM1 and Orai1 endows the typically non-invasive human mammary epithelial cells with the capability to infiltrate Matrigel. This unexpected outcome implies a potential avenue for SOCE activation in transforming non-invasive epithelial cells into invasive variants.

IP3Rs, prominently expressed on the ER membrane, have also substantial roles in cancer progression by manipulating various cellular processes including autophagy, apoptosis, proliferation, migration, and invasion by reorganizing the actin cytoskeleton [56, 57]. In particular, in human breast cancer cells, silencing IP3Rs in cells results in changes in the spatial distribution of F-actin and the expression level of profilin, leading to decreased adhesion of cancer cells and causing the cells to adopt a rounded shape.

By influencing intracellular calcium levels and activating calcium-dependent signaling pathways, these channels modulate the remodeling of the actin cytoskeleton, focal adhesion turnover, and other processes crucial for cellular movement. Additionally, the involvement of calcium-independent mechanisms, such as direct interactions with signaling molecules like FAK, adds another layer of complexity to the regulation of cell migration by calcium channels. Furthermore, the identification and characterization of other calcium channel subtypes involved in cell migration, such as TRP channels, offer exciting avenues for future research and therapeutic intervention in cancer metastasis. Further exploration of the intricate interplay between calcium signaling and cell migration is necessary to uncover the precise molecular mechanisms underlying these processes and develop targeted therapeutic strategies to inhibit cancer cell migration and invasion. Collectively, these findings highlight the intricate relationship between calcium channels and cytoskeletal proteins to regulate cell migration, emphasizing the need for further research to unravel the specific roles of different calcium channel subtypes in tumor progression.

4. Calcium channel blockers as a potential therapeutic approach in cancer

Calcium channel blockers (CCBs), long-established pharmaceutical agents for managing cardiovascular ailments like hypertension and angina, work by inhibiting the influx of calcium into myocardial and arterial wall cells. This action promotes vasodilation and relaxation, consequently decreasing blood pressure and reducing cardiac workload [58]. In a new research direction, CCBs are being examined as potential cancer therapeutics due to the significant role calcium ions play in cancer progression. Indeed, calcium ions have been found to be pivotal in various aspects of tumorigenesis and cancer progression, including cell proliferation, apoptosis (programmed cell death), angiogenesis (the formation of new blood vessels), and metastasis (the spread of cancer from the primary site to other parts of the body). In the context of metastasis, particularly to bones, the role of calcium becomes even more pronounced. Bones are frequent targets of metastasis for several cancers, notably breast and prostate cancer. As tumor cells invade bone tissues, they disrupt the delicate balance between osteoblasts and osteoclasts, leading to an exacerbated bone resorption [59]. This process not only releases essential minerals that nourish tumor cells but also escalates calcium levels in the bloodstream, known as hypercalcemia. Elevated calcium can act as signaling molecules that further promote tumor cell survival and proliferation within the bone microenvironment [60]. Therefore, understanding calcium signaling in osseous metastatic disease is critical. Modulating the concentration of these calcium within cellular environments might very well hold the key to a promising new strategy in the ongoing fight against cancer.

Supporting this hypothesis, several in vitro and in vivo studies suggest that CCBs effectively suppress the migration, invasion, and proliferation of cancer cells. One example is that CCBs can act as potent inhibitors of filopodia formation by cancer cells, essential for cancer cell migration and metastasis [61]. Filopodia are thin, finger-like protrusions on the surface of cells that play a crucial role in cell motility and invasion. By inhibiting filopodia formation, CCBs can potentially impede the ability of cancer cells to migrate and invade surrounding tissues. Although the full understanding of how CCBs inhibit cancer cell invasion and proliferation, one hypothesis is that the L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signaling. Integrins, critical cell surface receptors involved in cell adhesion and migration, may have their function disrupted by the inhibition of these calcium signaling. Additionally, CCBs have been reported to decrease tumor viability and trigger apoptosis in various cancer cell lines. Apoptosis is a programmed cell death process that helps to eliminate damaged or abnormal cells. By inducing apoptosis in cancer cells, CCBs may contribute to the suppression of tumor growth.

The proposed rationale for these effects largely hinges on the ability of CCBs to obstruct the entry of calcium ions into cells, thereby affecting the dynamics of the actin cytoskeleton. Given the critical role of the actin cytoskeleton in cell division and movement, blocking calcium influx could potentially disrupt these vital cellular processes and inhibit the propagation of cancer cells. In recent advancements in the calcium-cancer nexus, the calcium-sensing receptor (CaSR), a G-protein coupled receptor, has been highlighted. Predominantly known for its roles in the parathyroid gland and kidneys [62] to maintain calcium homeostasis, its presence on various cells, including certain cancer cells, has been elucidated. Particularly in the context of osseous metastatic disease, the activation of CaSR can influence bone remodeling processes, often dysregulated in skeletal metastases. Some studies suggest that in specific cancer types, CaSR activation might enhance tumor cell proliferation, migration, and survival [63, 64]. This emerging understanding underscores the potential of targeting CaSR as a therapeutic strategy, further emphasizing the intricate relationship between calcium signaling and cancer progression.

CCBs have also garnered attention in cancer research due to recent investigations suggesting their potential role in limiting angiogenesis—the formation of new blood vessels. Given the heavy reliance of tumors on angiogenesis for a consistent supply of nutrients and oxygen, the ability of CCBs to obstruct this process could have profound implications on restricting tumor growth and size. Several studies have investigated the use of CCBs in cancer-related angiogenesis. One study discovered that antihypertensive drugs, including CCBs, could either facilitate or interfere with tumor cell proliferation, migration, apoptosis, and angiogenesis [65]. They highlighted the role of CCBs in regulating the expression of vascular endothelial growth factor (VEGF), a key player in angiogenesis. Studies examining the impact of L-type and T-type CCBs on angiogenesis has demonstrated that verapamil, an L-type CCB, exhibited promising anti-angiogenic properties [66]. Further, several studies have highlighted the regulation of calcium entry as a potential therapeutic approach with significant potential in managing cell proliferation, particular with respect to angiogenesis [67, 68].

Extending from the prospect of calcium entry regulation as a therapeutic approach, CCBs have also been investigated for their role in overcoming drug resistance in cancer treatment. Multidrug resistance significantly undermines the effectiveness of chemotherapy in cancer treatment. One prevalent theory suggests that CCBs may interrupt the function of certain efflux pumps, such as P-glycoprotein and multidrug resistance-associated proteins. Theses pumps actively eject therapeutic drugs from cancer cells, thereby reducing their efficacy. By inhibiting these pumps, CCBs could conceivably enhance the intracellular concentration of chemotherapy drugs, thereby intensifying their cytotoxic effects on cancer cells. Supporting this notion, studies have demonstrated enhanced survival rates in anthracycline-resistant metastatic breast cancer when the CCB verapamil was administered alongside chemotherapy [69] . Likewise, studies reported that CCBs, such as verapamil and amlodipine, could potentially counteract drug resistance in tumors that are expressing multidrug resistance proteins [70, 71].

It is crucial to consider that the impact of CCBs on cancer cells may not be uniform, but instead dependent on the particular type of cancer and the cellular environment. In addition, there have been studies suggesting potential risk of myocardial infarction in hypertensive patients [72, 73]. Despite these potential risks and the limited current evidence, the studies mentioned above underscore the potential of CCBs as a promising, multi-faceted approach to cancer therapy. As our understanding of the relationship between calcium ions and cancer progression deepens, the role of CCBs may continue to evolve and expand within the realm of oncology.

Even though these studies offer promising initial results, the exact mechanisms through which CCBs exert their anti-cancer properties are not yet entirely clear and warrant further study. The complexity of calcium signaling in cancer cells, together with the numerous calcium channel subtypes, poses a complex and challenging research question. Understanding how CCBs might interact with other cancer therapies and identifying specific cancer types or stages of disease where CCB therapy could be most effective is also crucial. As is true for all potential new therapies, the safety and effectiveness of CCBs are of paramount importance. While it is well-documented that patients with cardiovascular diseases typically tolerate CCBs well, their impact when used for cancer treatment remains largely unexplored. Comprehensive evaluation of potential side effects, and determination of optimal dosage and treatment regimen require additional large-scale clinical trials. Some CCBs may enhance the effectiveness of chemotherapy drugs, particularly in drug-resistant tumors, by increasing their intracellular concentration. However, there is also the risk that certain CCBs could interfere with chemotherapy drug metabolism, potentially increasing toxicity. Initial findings suggest that cancers like breast and prostate might be more responsive to CCBs, especially given their propensity for bone metastasis. Yet, the challenge remains that continuous CCB use might lead tumors to develop resistance, emphasizing the necessity for adaptive treatment strategies. Ultimately, personalized treatment approaches, considering cancer type, stage, and genetic specifics, will be pivotal in optimizing the use of CCBs in oncological regimens.

In conclusion, the idea of repurposing CCBs, originally designed for managing cardiovascular diseases, as a potential therapeutic strategy for cancer presents a potentially exciting new direction in cancer treatment. However, substantial research still lies ahead. Comprehensive preclinical and clinical investigations are necessary to fully elucidate the mechanisms at play, pinpoint the types of cancer that could respond favorably to CCB therapy, and establish the safety and effectiveness of CCBs in this potential new role.