Abstract
Cancer remains one of the fatal diseases in the last century. The mortality rate of different types of cancer is mainly related to metastasis, where the traveling cancer cell clusters migrate to other organs and create a micro-metastatic niche. To date, most of the conventional and approved anticancer drugs belong to the cytostatic and cytotoxic categories. Cancer cells’ transcriptional and behavioral plasticity made traditional therapy futile in terms of stopping the spread and relapse of the disease. The recent emergence of drug-resistant cancers requires a new class of drug molecules. In this context, the potential of antimetastatic or migration inhibitory drugs is neither evaluated nor validated correctly. This chapter will introduce a new class of synthetic drugs that could be used to inhibit cancer cell migration and discuss their untapped potential as therapeutic agents. Migrastatic drugs working against multiple targets could successfully deter the tumor cells from initiating migration and bypassing the therapeutic effects. In the future, these new classes of antimetastatic compounds combined with conventional drugs could establish a new and improved treatment regime.
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Keywords
Introduction
In the last few decades, due to increasing pollution and changing lifestyles, cancer has become one of the major causes of death. The mass of cancerous cells, a consortium of heterogeneous population, exert their pathophysiological effects in many different ways, which are classified as cancerous hallmarks. One of the most crucial hallmarks of cancer is metastasis happens during the later stages of the tumor development. During this process, tumor cells from the primary source migrate to the neighboring organs to presumably establish secondary tumor sites. Metastasis is assumed to be one of the major reasons for the disease recurrence and cancer-associated mortality (Tan et al. 2015; Alizadeh et al. 2014). This process includes invasion of extracellular matrix by the solitary or cluster of cancer cells, intravasation, extravasation, and colonization of vital organs (Steeg 2006). Numerous studies have proved that cancer cells utilize different migration modes with plasticity during the invasion of ECM and intravasation, which facilitate their advancement in the ECM and the bloodstream. Multiple cellular and stromal components associated with cell migration, such as the cytoskeleton, matrix-degrading enzymes, kinases, and adhesion proteins, make the process of metastasis seamless. During this process, the cells also produce various cellular protrusions, namely, lamellipodia, invadopodium, and dendritic spine-like structures, to enhance migration speed and efficiency. Such arrangements play a crucial role in the remodeling and degradation of the ECM to allow cancerous cells to reach the bloodstream (Yamaguchi et al. 2005).
Metastasis Modality
Conventionally cancer cell migration mode can be divided into two broad classes, namely, collective and individual. Collective migration is defined by the migration of cellular clusters interconnected by adhesion molecules and other communication junctions. These clusters with leading and following edges penetrate the surrounding tissues through blunt cellular force supported by secretory and membrane-bound MMP-mediated degradation of ECM. Once the cell decides to migrate collectively, cell polarization occurs, leading to the formation of pseudopods. The pseudopods activate the integrin receptors and recruitment of scaffold proteins, forming nascent focal adhesions. These focal adhesions further mature and connect with the actin filaments. Molecules such as MT1-MMP and uPA/uPAR are recruited to execute the local proteolysis to break the ECM molecules and generate space for the cells to move ahead. The group of collectively migrating cells develops dynamic cytoskeletal structures which includes actin stress fibers comprising of actin and myosin light chain. These stress fibers at the leading edge generate the necessary traction force to move the cellular mass forward. These leader cells remain connected to the other trailing cells through cell-cell interactions. The trailing edge forces the cell-to-cell junctions and focal adhesion complexes between, to drag the neighboring cells along the migration track (Friedl et al. 2004).
On the other hand, migration of individual cancer cells through the ECM is mainly classified depending on their dependence on protease such as mesenchymal (protease dependent) and amoeboid (protease independent) migration. These modalities can switch depending on the cellular and environmental cues and the tumor microenvironment (Gayan et al. 2021; Krakhmal et al. 2015). Such plasticity is an intrinsic virtue of cancer cells which allows the development of variable modes of migration, namely, epithelial-mesenchymal transition (EMT), mesenchymal-epithelial transition (MET), ameboidal-mesenchymal transition (AMT), and mesenchymal-ameboidal transition (MAT) during metastasis. EMT occurs at the primary tumor site, where the tumor cells detach from the epithelial layer of the tumor mass to achieve mobility. Whereas MET, (the counter transition) happens when the tumor cells stop at another organ and differentiate to establish a secondary tumor site (Vasiliev and Gelfand 2006). The characteristic features of EMT include the loss of apicobasal polarity, loss of cell adhesion molecules like E-cadherins, and cytoskeletal rearrangement for the formation of stress fibers (Micalizzi et al. 2010). As observed, different key transcription factors including TWIST1, Snail, Slug, and ZEB1/2 are responsible for initiating EMT (Tsai et al. 2012). Through the EMT transitions, tumor cells perform intravasation and spread to different tissues and organs. After reaching the metastatic loci, these migratory cells return to their epithelial phenotype through MET. This phenomenon occurs through the inhibition or decrease of the factors directly involved in the EMT (Nguyen et al. 2009).
Other modalities of single-cell migration like AMT and MAT are also tightly regulated through the interaction of tumor cells with the tissue microenvironment but observed more rarely (Gayan et al. 2021). AMT has the same molecular basis as MAT, and reversal of conditions leads to AMT. The primary process behind MAT transition, as explained by Friedl, includes membrane protrusion, reduction in pericellular proteolysis, the absence of p27 protein, reduced integrin receptors’ activity, and increased GTPase Rho activity A (Friedl 2004). The formation of membrane protrusion is influenced by the localized polymerization of submembrane actin filaments. WASP family proteins, LIM-kinase, cofilin, and cortactin are some of the critical proteins upregulated in invasive and metastatic cancer cells. These are responsible for actin cytoskeletal reprogramming towards a migratory phenotype (Sahai 2005; Yamaguchi et al. 2005). These proteins are responsible for the Arp2/3 complex-dependent nucleation for the dendritic/protrusion phenotype developed by cancer cells. Cortactin and cofilin are required to stabilize these branched filaments/protrusions (DesMarais et al. 2004). Minimal expression of cell adhesion molecules such as E-cadherin and α-catenin leads to the increased metastatic potential of the tumor. Re-localization of β-catenin to the cell nucleus from cytoplasm is positively associated with the mesenchymal phenotype required for single cellular migration (Jiang 2005). The reduced expression of cell adhesion protein directly co-related with the increased function of matrix metalloproteases (MMPs) which is necessary for degrading various extracellular matrix proteins to ensure cell motility during metastasis. Transcription factors including tumor growth factor β (TGFβ) and epithelial growth factor (EGF) induce MMP production to enhance cell motility (Xu et al. 2010). Kinases of the Src family, especially c-Src, play a supportive role in tumor metastasis in colorectal and breast cancers (Summy and Gallick 2003) through mutations, chromosomal translocation, and epigenetic deregulation mediated malfunctioning (Cicenas et al. 2018).
Main Text
Current Therapeutic Regime and Problems
The conventional therapeutic approach towards solid tumors and other types of cancer has been primarily inclined towards cytotoxic drugs paired with surgery and radiation therapy. These cytotoxic drugs differ in their mode of action and majorly include anti-metabolites, alkylating agents, topoisomerase, mitotic inhibitors, antibiotics, and lastly corticosteroids (Huang et al. 2017). Alkylating agents damage the cellular DNA, thereby preventing DNA replication and progression of the cell cycle. These drugs are commonly used to treat different types of aggressive cancers, including sarcomas, carcinoma, and lymphomas. A subcategory of alkylating agents called nitrosoureas includes lomustine and carmustine which can cross the blood-brain barrier (Gate and Kenneth 2011). Anti-metabolites interfere with the nucleic acids and replace their nucleotides to inhibit the replication process. Anthracyclines interfere with DNA synthesis preventing cell reproduction. Topoisomerase inhibitors (plant alkaloids) interfere with enzymes such as Topoisomerases I and II. Mitotic inhibitors inhibit cell division and induce apoptosis. These cytotoxic drugs are part of the decade-old treatment regime for most aggressive cancers despite multiple side effects and the eventual development of resistance.
Cytotoxic drugs could not differentiate between normal and target cells; hence prolonged use of cytotoxic drugs can have toxic side effects on other tissues and organs of the body (Table 1). Most of these cytotoxic drugs are very efficient in the late tumor stages. However, they have many significant deleterious effects, including hair loss, skin rash, anemia, and others. Other minor side effects such as nausea and vomiting are also common occurrences (Nurgali et al. 2018). Further, there is a risk of hypersensitivity reactions against various cytotoxic drugs in the system (Ruggiero et al. 2017).
Along with the patients, many unintended targets such as healthcare workers can be exposed to these agents. For example, studies reported health workers handling cytotoxic drugs with increased risk of leukemia and breast cancer. Unintended exposure to these drugs may also occur during the preparation, administration, and transport of the drug along with the disposal of the organic waste. Other sources of environmental contamination include patient excreta and secretions (Alehashem and Baniasadi 2018).
Along with the unwanted side effects and unintended contaminations, developing resistance against those drugs is also becoming a point of concern. The critical factors influencing the resistance are physical barriers, tumor burden, and tumor heterogeneity, TME (tumor microenvironment), TIME (tumor-immune microenvironment), and therapeutic pressures (Vasan et al. 2019). Cancer heterogeneity caused by genomic instability, transposition, translocation, microRNA, and epigenetic factors generates chronic drug resistance and poor prognosis (Mansoori et al. 2017). The tumor’s heterogeneous microenvironment and the different cells like the immune cells and stromal cells prevent immune clearance and drug absorption. Immunosuppressive cancer microenvironment consists of different cellular (Treg cells, natural killer cell, and tumor-associated macrophages) and acellular components (cytokines and chemokines) majorly influence the effectiveness of anti-tumor drugs (Sharma et al. 2017). Long-term therapies can also lead to resistance, and it could be an early adaptive response or resistance acquired after prolonged exposure (Mok et al. 2017). The adaptive response happens due to negative feedback-mediated activation of the alternative metabolic pathways or reactivation of the initial ones. Acquired resistance happens with the emergence and accumulation of new mutations of the target followed by the diversion of pathways and changes in phenotypes (Vasan et al. 2019).
Drug resistance is the most significant hurdle in cancer treatment and seems to be an unattainable goal. These disadvantages pose a problem for commonly used cytotoxic drugs and make it necessary to develop a new genre of drugs targeted explicitly towards cancer. Recently, a unique class of molecules referred to as migrastatic is recognized as a potential mode of therapy. Effectivity of cytotoxic or cytostatic drugs is measured quantitatively through tumor shrinkage, which is assumed as the main criteria in the current world of cancer therapeutics. With the emergence of drug resistance cancers, it is proposed that the importance of tumor shrinkage as the main criteria of drug efficacy should be revisited. The hour needs a critical understanding of the holistic effect of the used drug and its intended effectiveness (Fernandes et al. 2019). Deep analysis of the physical properties of the tumor, dependencies and vulnerabilities, and personalized study of the patient is required to solve the current problems.
Migrastatics: A New Class of Drugs
Even though metastasis is the deadliest aspect of a tumor, no antimetastatic drugs are available to date as a treatment modality. The main aim behind developing the migrastatic molecules is to prevent local and global invasion. The term migrastatic has been proposed for molecules that target pathways involved in cell migration and interfere with different modalities of migration, thus inhibiting invasion, extravasation, and colonization (Gandalovicova et al. 2017). They do not directly affect cell viability but impede tumor cell dissemination and further migration.
The dissemination of cancer cells initiated by the destruction of the cell-cell adhesions followed by the conversion of E-cadherin to N-cadherin provoke cell migration and invasion. The cadherin switch induces reorganization of actin filaments and degradation of extracellular matrix through matrix metalloproteinases. Migration of a single cell involves activation of multiple cell and substratum adhesion molecules along with the change of cell-polarity and cytoskeletal arrangement (Yilmaz and Christofori 2010). Migrastatic drugs are proposed to target molecular mechanisms that are common and essential in cancer cell migration and cannot be bypassed. Therefore, the ultimate downstream effectors like actin polymerization and contractility are targeted as prime candidates. Cancer cell migration and invasion culminate in actomyosin contractility and actin polymerization, irrespective of the migration modality (Gandalovicova et al. 2017).
Inhibitors of these processes from natural sources are available, which has been proposed in the past as potential migrastatic agents (Table 2) (Gandalovicova et al. 2017) (Gandalovičová et al. 2020). However, many synthetic compounds developed against such targets can also be classified as migrastatics depending on their function. This chapter will discuss the potential targets for such synthetic migrastatic molecules and focus on few therapeutic agents for future experimental evaluation and validation.
Potential Targets for Migrastatic Compounds
Metastasis is a process that requires different cellular components, including cytoskeletal proteins, focal adhesion proteins, and enzymes, which could have been potential targets for the migrastatic molecules (Fig. 1).
Cytoskeletal Proteins
Cytoskeletal proteins, namely, the microtubules (MTs), microfilaments (MFs), and intermediate filaments (IMFs), are involved in many cellular processes, including migration. Microtubules, the heterodimers of α- and β-tubulins, are consisting of different isotypes. Different isotypes of tubulin and microtubule-associated proteins (MAPs) contribute to cancer progression and chemoresistance. Microfilaments are polymers of actin protein, which exist either as in globular monomers (G-actin) or in the polymeric filamentous form (F-actin). The continuous turnover between these two states controls the migration status. An increment in the ratio of globular-filament actin promotes metastasis in cancerous cells. Actin filaments interact with myosin to form actin stress fibers, which participate in cancer cell migration. Intermediate filaments including different polymers, namely, cytokeratin, vimentin, desmin, glial fibrillary acidic protein, neurofilaments, nuclear lamins, and nestins, are also involved in cell migration. Epithelial to mesenchymal transition (EMT) is promoted by reorganization of intermediate filaments, leading to migration, acquiring a metastatic trait. Another class of cytoskeletal proteins, including cell adhesion molecules (CAM), catenin, and actin-related proteins, also plays a significant role in cytoskeletal re-organization (Ong et al. 2020). Direct inhibitors of the polymerization and depolymerization process of cytoskeletal protein can be regarded as potential migrastatics.
Actin-Related Proteins
Seamless turnover of cytoskeletal proteins through polymerization and depolymerization is critical for migration. Several proteins such as Arp2/3, WASP, cofilin, and others participate and maintain the cytoskeleton turnover rate as required. Arp2/3 nucleates the newly formed actin filament and creates a branched network. Members from the WASP family (Wiskott–Aldrich syndrome protein) protein help in the activation of Arp2/3 and actin polymerization (Millard et al. 2004). Cofilin is another essential regulator of actin dynamic, nucleating actin polymerization. It facilitates the process of cell migration by interacting with both monomeric and filamentous actin. LIM kinases are the upstream regulator of cofilin, which phosphorylate, and inactivate cofilin. Cofilin and LIM kinases have been observed to regulate cancer cell motility (Zebda et al. 2000). Cortactin can serve as another potential migrastatic target as it binds and cross-links with actin filament. It directly initiates the nucleation activity of Arp2/3 and stabilizes the newly formed branched actin filament (Yamaguchi and Condeelis 2007). Tropomyosin binds to the helical groove of the actin filament and stabilizes the filament actin. Tm5 (hTm5NM1), another isoform of tropomyosin, recruits myosin II into actin stress fibers. Another isomer, TmBr3, binds to cofilin and participates in migration (Bryce et al. 2003). Inhibition of these proteins can disturb the cytoskeletal turnover successfully and, hence, function as a potential target.
Focal Adhesion Complex Protein
Protein molecules involved in the formation of physical connection between cell-extracellular matrix or cell-basement membrane are critical regulators of cell migration. First, of such molecules, integrins (different isoforms of a and b types) mediate the cellular contact with the ECM components such as fibronectin. Those nascent structures also recruit other adaptors/scaffold proteins like talin, paxillin, tensin, p130Cas, and α-actinin to stabilize the focal adhesion complex. Stable focal adhesion complexes generate the necessary contractile force and tension through actin stress fibers (Nagano et al. 2012). Small molecule inhibitors or active site-specific antibodies against focal adhesion complex proteins can successfully inhibit their participation in migration and function as potential migrastatics.
Enzymes and Signaling Protein
Along with the scaffold proteins, multiple enzymes, including kinases, phosphatase, and proteases, also play essential role during both collective and single-cell migration. Signaling proteins like tyrosine kinases, Src kinases, and focal adhesion kinase (FAK) play a vital role in the substratum integrin-mediated signaling cascades. They transmit the ECM-derived signal to cellular pathways controlling cell migration through phosphorylation/dephosphorylation of their targets (Nagano et al. 2012). Protease enzymes, an essential component behind cancer cell invasion and multi-drug resistance, could be another candidate for migrastatics. Different classes of proteases, including matrix metalloproteases, serine, threonine, cysteine, and aspartate, help to degrade and remodel intracellular and extracellular matrix (ECM) proteins. The secretion of cysteine proteases accomplishes podosome-mediated degradation of extracellular matrix and invasion. Serine proteases like matriptase are actively involved in the process of angiogenesis and degradation of extracellular matrix in some epithelial cancer. Cathepsin–D (Cath-D), an aspartic endo-protease, stimulating proliferation, angiogenesis, and metastasis, is categorized as a prognostic marker of breast cancer. Procathepsin D promotes the pro-invasive and pro-metastatic properties in both tumor and stromal cells (Rakash 2012). Matrix metalloproteinases (MMP) help to degrade the cell-matrix adhesions, thereby enabling cancer cells to migrate and invade (Martin et al. 2013). MMPs are also involved in the preliminary steps of tumor evolution, which include proliferation of cancer cells and angiogenesis. MMP induction also helps in invasive growth at the secondary site (Rakash 2012). Successful inhibition of these enzymes can minimize the migration potential of cancer cells; hence they can be regarded as potential targets for migrastatics.
Migration-Specific Small GTPase
During migration, cytoskeletal proteins primarily interact with the motor proteins (specifically myosin) to generate cell surface contractions. Among different classes of the myosin superfamily, non-muscle myosin II is known to play a critical role in cellular adhesion and migration (Vicente-Manzanares et al. 2009). The formation of the actomyosin couple depends on Ca + 2 efflux and the Rho family of small GTPase. Ca + 2-dependent functionalization of myosin light chain kinase (MLCK) leads to phosphorylation of myosin light chain (MLC) and formation of actomyosin complex (Chi et al. 2014). Small GTPase Rho A can also phosphorylate Rho-associated protein kinase (ROCK), which further phosphorylates MLC2. The phosphorylated MLC2 promotes actomyosin interaction followed by myosin ATPase activation (Pandya et al. 2017). ROCK can also activate LIM kinases leading to the inhibition of cofilin activity and blocking of actin depolymerization. Myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK), another effector of actomyosin interaction, can regulate pathways involved in cancer cell migration along with ROCK (Kale et al. 2015). Another membrane glycoprotein, gp38 (podoplanin or Aggrus,) controls actomyosin contractility in lymphoid fibroblasts and influences the migration (Quintanilla et al. 2019). Podoplanin also influences the cytoskeletal contractility, thus promoting invasive amoeboid morphology in melanoma cells (de Winde et al. 2020). These small GTPases play a critical role in migrational plasticity of cancerous cells and can be asserted as potential target for migrastatic agents.
Potential Migrastatic Compounds
Various known chemicals and pharmacologically active compounds are available, which can function specifically against the cell migration pathways and hence could be classified as migrastatics. Several molecules of natural origin are classified as migrastatics (Table 2) in previous studies (Gandalovicova et al. 2017; Gandalovičová et al. 2020). However, synthetic and semi-synthetic inhibitors with similar purposes have not been studied or classified in detail. Therefore, this chapter focuses on synthetic and semi-synthetic compounds and ascertains their role migrastatic (Fig. 2).
Myosin Inhibitor
Blebbistatin, a 1-phenyl-2-pyrrolidinone derivative, inhibits non-muscle myosin II activity, which is required for force generation and contractility during cell migration. It binds with the myosin-ADP-Pi complex and inhibits the release of the phosphate group. Thus, blebbistatin stabilizes myosin II in an actin-devoid state and inhibits actomyosin crosslinking (Kovács et al. 2004). Recent reports show that it inhibits pancreatic adenocarcinoma (Duxbury et al. 2004) and E6 glioma cell (Ivkovic et al. 2012) invasion. In few studies, blebbistatin (5 μmol/L) impedes cell division and leads to G0/G1 arrest in mesenchymal stromal cells, which needs to be studied in depth (Sharma et al. 2014) to avoid un-intended cell death.
Arp2/3 Inhibitor
Actin-related protein (Arp2/3) complex interacts with existing actin filament and nucleates the development of branched filament. Small molecules (such as CK-666 and CK-869) bind to Arp2/3 and inhibit it (Nolen et al. 2009). CK-666 interact with both Arp2 and Arp3 and block their involvement in the activated filament conformation. CK-666 inhibits the migration of glioma cells (U251, LN229, and SNB19) (Liu et al. 2013). In prostate cancer cells (DU145), CK-666 did not affect the actin cytoskeletal structure and the mechanical properties of the cells but impaired their motility (Efremov et al. 2015). C-869 binds to the hydrophobic core of Arp3, destabilizing the active site (Hetrick et al. 2013). However, inactivation of Arp2/3 is not enough to influence the cell motility in all types of migratory cells, as CK-666 could not inhibit the migration of A2780 ovarian carcinoma cell (Paul et al. 2015). Another small molecule, Pimozide, belonging to the diphenylbutylpiperidine group of drugs, targets dopamine receptor D2 (DRD2) to reduce cell migration and the dissemination of xenograft tumors in the mice (Jandaghi et al. 2016). Pimozide also interacts with ARPC2 and inhibits actin polymerization, leading to the disappearance of lamellipodia and inhibited migration. It resulted in detectable cytotoxicity and could be categorized as valuable a migrastatic (Choi et al. 2019).
Similarly, benproperine (Benp), an FDA-approved antitussive drug, can block tumor cell dissemination in pancreatic and colorectal cancers through ARPC2 binding. In addition, in liver metastasis model, Benp significantly inhibited the metastasis of colon cancer to the liver (Yoon et al. 2019). Thus, these molecules can suppress tumor growth and dissemination into the major organs like the liver, kidney, and colon, as observed in an orthotopic mouse model.
Tropomycin Inhibitor
Development of anti-tropomycin compound targets different isoforms of tropomyosin and effective against melanoma, neural crest-derived tumor cell lines, and neuroblastoma cells. At a sublethal dose of 3 mmol/L, TR-100 impacted the migration of cancer cells in the 2D and 3D conditions (Stehn et al. 2013). In addition, this lead compound shows minimal effect on cardiac cells, which is a matter of concern for anti-actin drugs.
Inhibitors of Rho-Kinase (ROCK)
Fasudil (1-(5-isoquinolinesulfonyl)-homopiperazine) is the first developed inhibitor of Rho-kinase, (Yamaguchi et al. 2006) and inhibits the progression of tumor in the syngeneic peritoneal dissemination model, lung metastasis model, and the breast cancer orthotopic model. The prodrug Fasudil gets converted to 1-(hydroxy-5-isoquinoline sulfonyl-homopiperazine) (fasudil-OH) after the cellular entry and interacts with the phosphate loop of Rho-kinase. The prodrug showed more potency in inhibiting the migration of MDA-MB-231 and HT1080 cells (Ying et al. 2006). It also successfully inhibited the migration of urothelial cancer cells (5637 and UM-UC-3) (Abe et al. 2014) and breast cancer cell (MDA MB 231) (Guerra et al. 2017). Another ROCK kinase inhibitor Y-27632, a pyridine derivative, inhibits actomyosin contraction (Uehata et al. 1997) and disrupts tumor cell motility and chemotaxis in human prostate cancer cell lines (Somlyo et al. 2000). Y27632 treatment also reduced in vitro and in vivo breast cancer migration to bone (Liu et al. 2009). However, in a contradictory report, ROCK inhibition is observed to promote migration of breast cancer cells (MCF-7) in both 2D and 3D environments (Yang and Kim 2014). Y27632 blocked the migration of human tongue squamous cell carcinoma cells (Tca8113 and CAL-27) (Wang et al. 2016). Similarly, another ROCK kinase inhibitor, PT-262 (7-chloro-6-piperidin-1-yl-quinoline-5,8-dione), a derivative of 5,8-quinolinediones, induces cytoskeletal remodeling. It inhibits ROCK-mediated phosphorylation of the MLC and formation of stress fibers, thus inhibiting migration of lung carcinoma cells. In A549 lung carcinoma cells, PT-262 is found to be more effective than Y27632 or H-1152 (Tsai et al. 2011). Another inhibitor of ROCK RKI-1447 binds to the ATP site of ROCK 1 and selectively inhibits the phosphorylation of ROCK substrates such as MLC-2 and MYPT-1. It is seen to inhibit tumor growth and initiates tumor regression in ErbB2-driven breast cancer mouse model. It inhibits migration and mammosphere formation of breast cancer cells (MDA-MB-231 and MDA-MB-468) and lung cancer cell line (H-1299) (Patel et al. 2012). A multikinase inhibitor DJ4 {(5Z)-2–5-(1H-pyrrolo[2,3-b] pyridine-3-ylmethylene)-1,3-thiazol-4(5H)-one} selectively inhibits the Rho-kinases, ROCK1, and ROCK2 in addition to myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKα and MRCKβ). DJ4 significantly blocked the formation of stress fibers and inhibited cell migration in non-small-cell lung cancer (A549, CCL-185; H522, CRL-5810; H23, CRL-5800; H2126, CCL-256; H460, HTB-177), melanoma (A375M, CRL-1619), pancreatic cancer (PANC-1, CRL-1469), breast cancer (MDAMB-231, HTB-26), and glioblastoma (U251) cell lines. Combined inhibition of ROCK and MRCK has a much potent effect in inhibiting metastasis compared to the inhibition of either kinase individually, which may hold DJ4 as a more promising migrastatic drug across a broad spectrum of cancer types (Kale et al. 2015). CCT129254 and AT13148 are another class of AKT inhibitors that also inhibits ROCK 1 and ROCK 2. They impair both amoeboid and mesenchymal modes of invasion in melanoma cells and inhibit cell proliferation (Sadok et al. 2015).
Actin Filament-Related Inhibitor
Inhibition of actin polymerization through synthetic and semi-synthetic molecules emerges as a critical approach for migrastatic. A synthetic actin inhibitor MKT-077 (1-ethyl-2-[[3-ethyl-5-(3-methyl-2(3H)-benzothiazolylidene)-4-oxo-2-thiazolidinylidene] methyl]-pyridinium chloride) shows antitumor activity in cancer cell lines like colon carcinoma (CX-1), breast carcinoma (MCF-7), pancreatic carcinoma (CRL142O) (Koya et al. 1996). It crosslinks with actin leading to the bundling of the actin filament and thus blocking membrane ruffling. In Ras-transformed neoplastic cells, it has the advantage of binding with p45 and p75 but not in normal parental cells (Tikoo et al. 2000). The semi-synthetic derivatives of Latrunculin, C-17 hydroxyl, and thiazolidinone nitrogen, inhibitors of actin polymerization, successfully modulate the binding affinity of G-actin. They exhibit anti-invasive effects in breast carcinoma (MDA MB 231 and MCF-7 cells) (Khanfar et al. 2010).
MLCK Inhibitor
MLCK-mediated phosphorylation of the myosin II influences its activity which leads to contraction, motility, and cytoskeletal remodeling. MLCK inhibitors such as ML-7 and ML-9 inhibit the phosphorylation of myosin regulatory light chain and activation of myosin II which prevents migration of rat prostatic adenocarcinoma (R-3327-AT-1) (Tohtong et al. 2003) and human glioma cells (U251MG) (Gillespie et al. 1999). ATPR (retinoid 4-amino-2-trifluoromethyl-phenyl ester), a synthetic retinoic acid derivative, downregulates the expression of MLCK and phosphorylation of MLC protein through the p38-MAPK pathway inhibiting the migration of breast cancer cells (MDA MB 231) (Wang et al. 2013). Another synthetic analog of all trans retinoic acid (ATRA) known as 4-HPR or fenretinide hinders migration of human liver cancer cells (HepG2) by inhibiting the activation and expression of MLCK (Zhang et al. 2018). Two synthetic derivatives of curcumin, ST03 (1,2-bis[(3E,5E)-3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidyl]ethane-1,2-dione) and ST08 ([4-[(E)-[(5E)-1-[2-[(3E,5E)-3,5-bis[(4-hydroxyazonylphenyl)methylene]-4-oxo-1-piperidyl]-2-oxoacetyl]-5-[(4-hydroxyazonylphenyl)methylene]-4-oxo3-piperidylidene]methyl]phenyl] azinic acid), exhibit migrastatic properties by inhibiting migration of the breast (MDA-MB-231) and ovarian cancer cell lines (PA-1) (Koroth et al. 2019).
Protein Enzyme Inhibitor
Synthetic inhibitors of cellular enzymes can also act as migrastatic molecules. For example, an inhibitor of histone deacetylase 3 (HDAC3), MI-192, is involved in tubulin’s epigenetic regulation and microtubules’ stabilization. It inhibits the migration of adult glioma cell (U251 and KNS42) spheroids embedded in collagen (Harmer et al. 2019). SL-1910 (N, N-dialkylthiazolo [5,4-b] pyridine-2-amine), a novel potent migrastatic drug, directly interacts with KRS (Lysyl-tRNA Synthetase). KRS, a Class II aminoacyl-tRNA synthetase, gets phosphorylated and stabilizes laminin receptor (67LR) in the laminin signaling pathway to stimulate cell migration. SL-1910 inhibits breast cancer cell migration in both in vitro (MDA MB-231) and in vivo 4 T1 xenograft metastasis models without detectable toxicity (Lee et al. 2021).
Probable Problems with Migrastatic Candidates as Anticancer Drugs
Irrespective of the successful preliminary reports, migrastatic compounds may have few drawbacks that need to be addressed before embracing them as a potential anticancer drug. Rigorous evaluation of these compounds needs a detailed analysis of their effect on different aspects of cellular behavior, including cell division, migration, cell-cell interaction, and others. Additionally, a functional model for metastasis is needed to assess their impact on migration pathways. Such a model should indeed recapitulate the cancer cell plasticity and include different modes of migration. Traditional 2D cell cultures that cannot incorporate such vast modalities should be replaced with advanced 3D and microfluidics models. The successful development of human-relevant 3D tumor models and tumor-on-chip is required to fill this gap.
Developing ideal xenograft models to screen migrastatics would be the next technical hurdle. Another problem would be the identification of predictable biomarkers and quantitative measures to analyze the expected effects. Developing advanced imaging tools to study the impact of drugs and monitoring metastasis in the in vivo model will be another matter of concern (Kale et al. 2015).
While choosing a target, all the undesirable effects of inhibiting the target should be kept in mind so that it does not cause harm to the cancer patient. As migrastatic drugs will be targeting cancer cell migration, the intermittent application will be anticipated. So, the requirement of low cytotoxicity should be a point of concern compared to conventional cytotoxic drugs (Gandalovicova et al. 2017). As migrastatic drugs will be targeting actin polymerization and cellular contractility without any specificity, the non-cancerous cell can also be a bystander target. Cells involved in migration such as stem cells, lymphocytes, macrophages, dendritic cells, fibroblasts, and others could be the unintended target for such molecules. Depending on the nature of the inhibitors (targets involved in the collective or single-cell migration), the “bystander effect” can be assumed and utilized to measure the toxicity score. For example, potential inhibitors of collective migration can inhibit typical wound healing within a cancer patient and delay the fibroblast-mediated scar tissue formation. Deregulation in cell migration may also lead to pathological conditions like inflammation (Pijuan et al. 2019).
Furthermore, such inhibitors may hamper other critical biological processes like gastrulation, organogenesis, neurogenesis, tissue homeostasis, and immune cell trafficking, which must be considered and weighed judiciously against the risk of metastasis.
Future Perspective and Conclusion
Migrastatics are a new class of drugs that primarily targets actin polymerization and contractility, the significant proponents of all kinds of cancer cell migration. The purpose of introducing migrastatic is not to completely replace cytotoxic or cytostatic drugs but rather to use them in synergy with other drugs. The therapeutic stratagem of combinatorial therapy using migrastatics with other traditional anticancer drugs might prove more effective in treating cancer while reducing chemoresistance and side effects.
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Gayan, S., Doshi, S., Dey, T. (2022). Synthetic Migrastatic: A New Class of Anticancer Drug. In: Chakraborti, S. (eds) Handbook of Oxidative Stress in Cancer: Therapeutic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-16-5422-0_266
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