Targeting E-cadherin expression with small molecules for digestive cancer treatment

Abstract

Digestive system cancers, mainly including gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer, are major public health problems and lead to serious cancer-related deaths worldwide. Clinically, treatment strategies of these cancers include surgery, chemotherapy, and immunotherapy. Although successful resection and chemotherapeutic drugs have improved the treatment level, the survival rate of patients with advanced digestive system cancers remains still low primarily due to tumor metastasis. E-cadherin, the prototypical member of the type-1 classical cadherins, has been characrized as an important molecule in epithelial-mesenchymal transition (EMT) process. Loss of E-cadherin is able to induce EMT process, which is associated with cancer stem cells and drug resistance in human cancer. Therefore, restoring E-cadherin could be a useful strategy for reversal of EMT and overcoming drug resistance. In this review, we describe pharmacological small molecules targeting E-cadherin expression for the treatment of digestive system cancers, which have emerged in the recent 5 years. We hope these compounds could be potentially used for treating cancer in the near future.

Introduction

Digestive system cancer (DSC) is one of the common leading causes for cancer-related death worldwide [1], mainly including gastric cancer (GC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and colorectal cancer (CRC). Current treatment strategies for these cancers include surgery, chemotherapy, and immunotherapy [2]. Despite successful resection or chemotherapeutic treatment, the survival rate of patients with advanced DSC remains still low primarily due to tumor relapse and metastasis [1-3]. In fact, tumor cell metastasis is a complex procedure in which numerous steps are involved, including local invasion and migration, dissemination of cancer cells through haematogenous or lymphatic pathways [3]. Therefore, it is essential to give a comprehensive understanding on the processes by which malignant tumor cells invade and metastasize to distant positions, which would be helpful to identify some potential therapeutic strategies for DSCs.

E-cadherin, known as the prototypical member of the type-1 classical cadherins, was first discovered as a cell surface molecule that mediated cell-cell adhesion in early mouse embryo blastomeres [4,5]. Structurally, E-cadherin contains a 120 kDa transmembrane glyprotein comprising five Ca²⁺-dependent extracellular domains (EC1-EC5), a transmembrane domain, and a cytoplasmic domain [6,7]. During the early stage of normal development, cells retain E-cadherin and adherens junctions (AJs) as both are vital for maintaining homeostasis and regulating cell-cell interactions of epithelia tissues. Epithelial-mesenchymal transition (EMT) is a fundamental morphogenetic process whereby epithelial cells acquire a mesenchymal phenotype [8]. Multiple studies have demonstrated that EMT is critically involved in tumorigenesis and cancer progression. Indeed, the expression of epithelial markers, in particular E-cadherin, is lost during the EMT process, leading to destructed cell-cell adhesion, increased cell motility and advanced stages of cancer [9-11] (Figure 1). Furthermore, cancer cells are able to acquire cancer stem cell (CSC) features via induction of EMT [12], resulting in increased drug resistance that limits the success of anticancer therapies [13,14]. Therefore, E-cadherin evolves as a promising therapeutic target for designing antitumor drugs. In this review, we will mainly focus on pharmacological small molecules targeting E-cadherin expression for treatment of DSCs, which have emerged in the recent 5 years.

Figure 1.

Illustration of E-cadherin structure and how EMT was initiated when E-cadherin expression is lost. E-cadherin is a transmembrane glycoprotein consisting of five calcium-dependent extracellular domains (EC1-EC5) that confer homotypic interactions on the surface of a neighboring cell, a transmembrane domain, and a cytoplasmic domain that binds to members of the catenin protein family to transduce physical and biochemical signals to the cell, including β-catenin and p120 catenin.

Regulation of E-cadherin expression in cells

The expression of E-cadherin is modulated at different levels including gene transcription and post-translational modification [15]. E-cadherin transcription is directly regulated by methylation of promoter activity. Methylation, known as a common modification of DNA induced by a family of DNA methyltransferase enzymes, directly regulates E-cadherin transcription via methylation of its promoter activity [16]. E-cadherin expression is significantly reduced due to promoter methylation, leading to the progression and metastasis in most human malignancies [17-19]. Src tyrosine kinase-mediated phosphorylation is considered as a major post-translational mechanism of E-cadherin expression and promotes the ubiquitination and degradation of E-cadherin [20]. Conversely, phosphorylation of E-cadherin at serine residues by GSK3β substantially increased the affinity of E-cadherin for β-catenin [21]. In tumors, the loss of E-cadherin is induced via activation of several signaling pathways involving oncogenic factors such as TGF-β, EGF, NF-κB, Wnt, and HIF-1α, thereby contributing to the formation of EMT [8,22] (Figure 2).

Figure 2.

Possible mechanism of E-cadherin in cancer cells. E-cadherin is a core regulator involved in tumorigenesis and cancer progression (metastasis and invasiveness, EMT, CSCs, and drug resistance).

Small molecules targeting E-cadherin expression in DSCs

Numerous emerging small bioactive compounds target E-cadherin expression and enhance the integrity of cell-cell adhesion in DSCs. However, for most of these molecules, clinical trials and applications need to be conducted in the future. In the following sections, we will describe a number of small molecules that could be used for DSC therapies due to restore the expression of E-cadherin, including the name, origin, and molecular mechanism by which these compounds exert their anticancer functions in DSCs (Table 1).

Table 1.

The list of small molecules targeting E-cadherin expression in DSCs

Compound	Description	Cancer	Mechanism and function	Reference
α-mangostin	A major xanthone compound in the pericarp of mangosteen	PC	Downregulates MMP-2 and MMP-9, inhibits the phosphorylation of ERK, increases the expression of E-cadherin, suppresses the ERK signaling pathway, inhibits cell invasion and migration	[59]
A novel phytosomal curcumin	A major component of turmeric	CRC	Increases the expression of E-cadherin, suppresses Wnt/β-catenin signaling pathway, inhibits cells growth and invasion	[74]
All-trans retinoic acid (ATRA)	An effective drug for the induction therapy of acute promyelocytic leukemia	HCC	Decreases the expression of N-cadherin, vimentin, Snail and Twist, increases the expression of E-cadherin, inhibits cells growth, colony formation, migration and invasion, reverses EMT	[48]
Antcin K	An active triterpenoid extract from Antrodia cinnamomea	HCC	Reduces integrin β1, β3, α5, and αv, suppresses phosphorylation of FAK, Src, PI3K, AKT, MEK, ERK, and JNK, reduces the expression and activity of MMP2, MMP9, and vimentin, upregulates E-cadherin, inhibits cell adhesion, migration and invasion	[35]
Anthothecol-encapsulated PLGA nanoparticles (Antho-NPs)	Anthothecol: a limonoid isolated from plant Khaya anthotheca; PLGA: poly D, L-lactic-co-glycolic acid	PC	Upregualtes E-cadherin, inhibits N-cadherin and ZEB1, suppress cells proliferation, colony formation, migration, and invasion, induces apoptosis, inhibits self-renewal capacity of CSCs	[62]
Arctigenin	A natural lignin compound	CRC	Increases E-cadherin, decreases N-cadherin, vimentin, β-catenin, Snail, MMP-2, and MMP-9, reverses EMT, inhibits cell migration and invasion, induces cell cycle arrest and apoptosis, suppresses lung metastasis	[79]
Arsenic trioxide (As2O3)	An anticancer drug for APL	HCC	Increases E-cadherin, decreases the levels of Snail, Slug, vimentin, and MMPs, attenuates the migration, invasion of cells	[49]
Berberine	A plant-derived isoquinoline alkaloid	CRC	Inhibits the transcriptional activity and expression of β-catenin, increases E-cadherin, inhibits Wnt/β-catenin signaling pathway	[72]
Brusatol	A natural quassinoid isolated from Bruceae Fructus	PC	Downregulates vimentin and Twist, stimulates the expression of E-cadherin, deactivates NF-kB, induces cell cycle arrest at G2/M phase and apoptosis, reduces tumor growth	[65]
Casticin	An active compound from Vitex Fructus	HCC	Increases the expression of E-cadherin, decreases the expression of N-cadherin and Twist, inhibits EMT process	[25]
Celastrus orbiculatus	A folk medicine in China	GC	Suppresses the NF-kB/Snail, downregulates Hsp27, vimentin, and N-cadherin, upregulates E-cadherin, attenuates TGF-β-induced EMT	[25]
Cinnamaldehyde (CA)	A bioactive compound isolated from the stem bark of Cinnamomum cassia	CRC	Upregulates E-cadherin, downregulates MMP-2 and MMP-9, inhibits PI3K/AKT pathway, induces apoptosis, inhibits cell invasion, adhesion, and proliferation	[71]
Cladosporol A	A secondary metabolite from Cladosporium tenuissium	CRC	Upregulates p21 and E-cadherin, promotes β-catenin nuclear export and proteasome degradation, inactivates β-Catenin/TCF signaling pathway, inhibits cell growth	[68]
Compound 3a	A naphthalimide derivative	HCC	Upregulates cyclin B1, CDK1, p21, and E-cadherin, inhibits migration and tumor growth, interrupts lung metastasis	[39]
Compound CH6	A compound derived from matrine	HCC	Upregulates P21, P27, and E-cadherin, downregulates N-cadherin, induces G1 cycle arrest, inhibits cell proliferation and migration	[37]
Sorafenib and vitamin K	Sorafenib: an oral tyrosine kinase inhibitor	HCC	Increases E-cadherin, reduces p-MET and p-ERK, inhibit HGF/c-MET pathway, inhibits proliferation, invasion and migration	[41]
Cordycepin	An analogue of adenosine from Cordyceps sinesis	HCC	Reduces FAK, integrin α3, α6 and β1, increases E-cadherin, inhibits cells proliferation, migration, and invasion	[43]
Curcumin	A major component of turmeric (Curcuma longa L.)	PC, CRC	Decreases Shh, GLI1 and vimentin, increases the expression of E-cadherin, inhibits cells proliferation, invasion and migration, induces apoptosis, reverses TGF-β-stimulated EMT	[53,77]
Curcumin and ulinastatin	Ulinastatin: a urinary trypsin inhibitor	CRC	Decreases MMP-9, increase E-cadherin, inhibits cell migration and invasion, inhibits hepatic metastases	[78]
Danusertib (Danu)	A pan-inhibitor of Aurora kinases	GC	Inhibits the PI3K/Akt/mTOR pathway, increases E-cadherin, decreases N-cadherin, induces G2/M arrest and apoptosis, inhibits EMT and cells growth	[26]
Diallyl trisulfide (DATS)	A natural compound extracted from garlic	GC	Increases cyclin A2, cyclin B1, JNK, ERK, and p38 phosphorylation, activates MAPK pathway, upregulates E-cadherin, downregulates MMP-9, inhibits cell proliferation, migration and invasion	[31]
Ellagic acid (EA)	A polyphenol found in several plants and fruits	PC	Inhibits Snail, MMP-2, and MMP-9, upregulates E-cadherin, suppresses Akt, Shh, and Notch pathways, inhibits cancer growth, angiogenesis and metastasis, reverses EMT	[54,55]
Embelin	A compound isolated from Embelia ribes	PC	Suppresses Akt, Shh, COX-2, VEGF, VEGFR, IL-8, MMP-2, and MMP-9, upregulates E-cadherin, inhibits Snail, Slug, and ZEB1, inhibit cancer growth, angiogenesis and metastasis, reverses EMT	[56,57]
Emodin	A anthraquinone derivative extracted from the root of rhubarb	CRC	Increases E-cadherin, decreases N-cadherin, Snail, β-catenin, MMP-7, MMP-9, VEGF, TCF4, Cyclin-D1 and c-Myc, inhibits Wnt/β-catenin pathway, tumor growth, cell invasion and migration	[73]
Ethanolic extract of bark from Salix aegyptiaca	Willow bark extracts	CRC	Restores E-cadherin, reduces EGFR, Snail1, Snail2, Twist, MMP-9, and MMP-2, inhibits cell growth, migration, adhesion, and EMT	[81]
Ethanolic extract of gamboge	A traditional Chinese medicine from gamboge	CRC	Decreases β-catenin, MMP-7, and cyclin D1, increases E-cadherin, inhibits cell proliferation and tumor growth, induces apoptosis.	[75]
Gadolinium chloride (GdCl3)	An injectable MRI contrast agent	HCC	Increases E-cadherin, reduces N-cadherin, Twist, Snail, and CD206, inhibits cells invasion, induces cell apoptosis	[50]
Galeterone (gal)/analogs (VNPT55, VNPP414, VNPP433-3b)	A multi-target chemotherapeutic agent in phase III clinical development	PC	Downregulates Mnk1/2, peIF4E, NF-κB, N-cadherin, MMP-1/-2/-9, Slug, Snail, CXCR4, β-Catenin, Nanog, BMI-1, Oct-4, and EZH2, upregualtes E-cadherin, induces G1 cell cycle arrest and caspase 3-mediated cell death, inhibits tumor growth, suppresses cell migration, invasion and proliferation	[64]
Hexa-D-arginine (D6R)	A suppressor of furin	PC	Upregulates E-cadherin, downregulates N-cadherin and vimentin, reduces the phosphorylation and expression of YAP, inhibits cell proliferation, migration and invasion	[66]
Hispidulin	A naturally existing flavonoid	CRC	Upregulates E-cadherin, inhibits Snail, Slug, and Twist, blocks PETN/PI3K/Akt pathway, inhibits cell motility, prevents hypoxia-induced EMT	[83]
Holy basil leaf extract	An extract from Holy Basil leaf	PC	Increases E-cadherin and BAD, downregulates ERK-1/2, FAK, p65, Bcl-2, Bcl-xL, AURKA, Chk1, and Survivin, inhibits cell growth, migration and invasion, induces apoptosis	[52]
Honokiol	A phenolic compound isolated from Magnolia grandiflora	GC	Increases E-cadherin, cytokeratin-18, and endoplasmic reticulum expression, decreases vimentin, snail, and Tpl2, reverses EMT, inhibits tumor growth and migration	[24]
Huaier	An antitumor drug	GC	Increases E-cadherin, decreases N-cadherin, TWIST and vimentin expression, reverses EMT, inhibits cell migration and invasion	[29]
Jianpi Huayu decoction (JHD)	A Chinese medicine	HCC	Decreases N-cadherin, Vimentin, and p-Smad3, increases Smad7 and E-cadherin, inhibits cell invasion, metastasis, and EMT process	[44]
Jianpi JieDu (JPJD)	An traditional Chinese medicine compound	CRC	Increases E-cadherin, represses vimentin, Snail, and p-Smad2/3, inhibits TGF-β/Smad pathway, inhibits EMT, cell invasion and migration, liver and lung metastases	[89]
LBH589	A new inhibitor of HDAC	HCC	Inhibits gankyrin/STAT3/Akt pathway, downregulate N-cadherin, vimentin, TWIST1, and VEGF, upregulates E-cadherin, inhibit cell growth and metastasis	[32]
Luteolin	A flavonoid present in fruits and green plants	GC	Induces E-cadherin, downregulates N-cadherin, vimentin, and snail, suppresses Notch1 signaling, reverses EMT, inhibits cell proliferation, invasion and migration	[27]
Matrine	A natural compound from the Sophora plant genus	HCC	Upregulates CAR, E-cadherin, laminin and fibronectin, inhibits the proliferation of cells	[36]
Meloxicam	A selective COX-2 inhibitor	HCC	Upregulates E-cadherin, Bax, and Fas-L, downregulates MMP-2, and Mcl-1, inhibits pAkt, inhibits cell invasion and migration	[33]
Metformin	An anti-diabetes drug	GC	Reduces vientin and β-catenin, induces E-cadherin, inhibits cell migration and invasion	[28]
MLN4924	An inhibitor of NEDD8-activating enzyme	GC	Activates E-cadherin, represses MMP-9, inhibits cullin 1 neddylation, suppresses tumor growth and migration	[30]
Nemopilema nomurai jellyfish venom (NnV)	A venom from Nemopilema nomurai jellyfish	HCC	Suppresses the activation of p-Smad3, Smad4, and p-NF-kB, downregulates N-cadherin and vimentin, upregulates E-cadherin and β-catenin, reverses EMT, inhibits cell invasion and migration	[46]
Niclosamide	An antihelminthic drug	CRC	Increases E-cadherin, inhibits Snail, disrupts Axin-GSK3 complex, reverses EMT, suppresses adenoma formation	[76]
Norcantharidin (NCTD)	An efficacious anti-cancer drug	CRC	Suppresses integrin αvβ6, MMP-3, MMP-9, F-actin, N-cadherin, vimentin, and ERK, upregulates E-cadherin, inhibits cell migration and invasion, induces MET process	[82]
N-trans-feruloyloctopamine (FO)	Originated from garlic skin	HCC	Inhibits the level of Akt, p38 MAPK, and Slug, increases the level of E-cadherin, inhibits cell proliferation and invasion	[38]
Nutlin-3	A small molecule regulator of p53	HCC	Increases E-cadherin level, decreases the levels of vimentin, Snail, Slug and Smad2, inhibits migration and invasion, suppresses EMT	[45]
Obatoclax	A pan-inhibitor of Bcl-2	CRC	Increases E-cadherin, p21, and p27, downregulates Cyclin D1, induces G1 arrest, inhibits cells migration, invasion and proliferation	[69]
Oxymatrine	An alkaloid extracted from the Chinese herb Sophora flavescens Ait	CRC	Increases E-cadherin, decreases PAI-1, TGF-β1, α-SMA, FN, Smad4, pSmad2 and pP38, inhibits TGF-β1/Smad pathway, and EMT	[88]
PNEE	Panax notoginseng ethanol extract	CRC	Decreases MMP-9, integrin-1, E-selectin, and ICAM-1, increases E-cadherin, inhibits cell adhesion, migration, and invasion	[70]
Physcion	An anthraquinone derivative	CRC	Increases E-cadherin, ROS production and pAMPK and GSK3β, decreases N-cadherin, vimentin, fibronectin, α-SMA, Snail, Slug, Twist, and SOX2, inhibits EMT, adhesion, migration and invasion	[84]
Pien Tze Huang (PZH)	A traditional Chinese formula	CRC	Increases E-cadherin, miR-200 fsmily, suppresses N-cadherin, ZEB1, ZEB2, TGF-β1, Smad2/3, and Smad4, modulate TGF-β1/ZEB/miR-200 pathway, inhibits cell proliferation, migration and invasion, induces apoptosis, inhibits tumor growth	[85,86]
Propofol	An intravenous anesthetic drug	PC	Decreases miR-21 and Slug, increases E-cadherin, inhibits cell growth and invasion, induces apoptosis	[63]
Resveratrol	A natural polyphenilic agent exists in grape and red wine	CRC	Upregulates E-cdherin, reduces vimentin and Snail, inhibits TGF-β1/Smads pathway, cells invasion and migration, inhibits lung and hepatic metastases, inhibits TGF-β1-induced EMT	[87]
Rosmarinic acid (RA)	A bioactive constituent from Rosemary	CRC	Upregulates E-cadherin, downregulates N-cadherin, Snail, Twist, vimentin, Slug, MMP-2, MMP-9, ICAM-1, and integrin β1, activates AMPK, inhibits cell adhesion, proliferation, invasion and migration, induce cell cycle arrest and apoptosis, inhibits lung metastasis	[80]
Rottlerin	A compound isolated from a medicinal plant Mallotus phillippinensis	PC	Suppresses Akt, Notch and Shh pathways, upregulates E-cadherin, inhibits COX-2, VEGF, VEGFR, IL-8, MMP-2, MMP-9, Snail and Slug, inhibits growth, angiogenesis and metastasis, induces apoptosis, reverses EMT	[58]
Sanguinarine	An alkaloid obtained from the root of Sanguinaria canadensis	PC	Upregulates E-cadherin, decreases N-cadherin, Snail, Slug, and ZEB1, suppresses SHH-Gil-Nanog pathway, inhibits cell proliferation, induces apoptosis, inhibits self-renewal capacity of pancreatic CSCs, reverses EMT	[60]
Scorpion	A wind calming drug	HCC	Increases E-cadherin, decreases N-cadherin and Snail, induces apoptosis, inhibits cell proliferation, migration, invasion, tumor growth, and metastasis	[51]
The anti-hTM4SF5 monoclonal antibody	A mAb of the cell surface transmembrane receptor	HCC	Increases the expression of E-cadherin and RhoA activity	[34]
Tunicamycin (TM)	An N-linked glycosylation inhibitor	HCC	Decreases CD44 and alters its glycosylation, Increases E-cadherin, suppresses CD44s- and TGF-β-mediated EMT, inhibits cells proliferation and migration, induce apoptosis and G2/M phase arrest	[42]
Ursodeoxycholic acid (UDCA)	A secondary bile acid	PC	Decreases the pSTAT3, inhibits Prx2, N-cadherin, Sox2, upregulates E-cadherin, reverses EMT, diminishes cancer stem cell formation	[61]
WZ35	A derivative of curcumin	HCC	Decreases MMP-2, MMP-9, and N-cadherin, upregualtes E-cadherin, promotes ROS-dependent JNK activation, suppresses proliferation, invasion, and migration	[40]

Gastric cancer

GC is one of the leading causes of cancer-related death worldwide with a poor response to current chemotherapy [23]. The anticancer effect of honokiol had been studied in GC. One group found that honokiol significantly inhibited invasion and migration of GC cells [24]. Further orthotopic mouse model studies revealed that honokiol-treated human GCs exhibited elevated epithelial biomarkers such as E-cadherin and cytokeratin-18 [24]. Conversely, reduced expression of vimentin, Snail and tumor progression locus 2 (Tpl2) was also noted [24]. Zhu et al. reported that celastrus orbiculatus effectively suppressed TGF-β1-mediated EMT in GC cells, which was further confirmed by upregulation of E-cadherin and downregulation of vimentin and N-cadherin [25]. Danusertib hampered EMT with an improvement in E-cadherin expression and a reduction in expression of N-cadherin in GC cell lines [26]. One group revealed that luteolin reversed EMT by promoting the expression of E-cadherin and reducing the level of N-cadherin, vimentin and snail, leading to inhibition of GC cell growth and metastasis [27]. Metformin ablated both the invasive and migratory ability of GC cells via repression of EMT in a glucose-independent way, as characterized by increased expression of the epithelial signature E-cadherin and decreased expression of the mesenchymal markers vimentin [28]. Huaier, a extensively used antitumor drug in China, presented a potent antimetastatic ability in GC cells partly via reversion of EMT as evidenced by upregulation of E-cadherin and downregulation of TWIST, N-cadherin, and vimentin [29]. A recently discovered inhibitor of NEDD8-activating enzyme (NAE), MLN4924, significantly suppressed neddylation modification activity and abrogated migration in human GC cells via transcriptionally facilitating E-cadherin and repressing MMP-9 [30]. Moreover, diallyl trisulfide (DATS), a natural compound extracted from garlic, suppressed GC growth and metastasis both in vitro and in vivo with no obvious adverse effects through activation of MAPK pathway and elevation of cytokine secretions, as accompanied by an increase of E-cadherin protein expression and a decrease of MMP-9 [31].

Hepatocellular carcinoma

HCC arises in patients as a consequence of long-standing preexisting liver illness, including viral hepatitis, alcohol abuse, or metabolic disease. Current standard practices for the treatment of HCC are unsatisfactory because of recurrence and metastasis [23]. LBH589, a new inhibitor of histone deacetylase, suppressed HCC metastasis both in vitro and in vivo without discernable adverse effects through an upregulation of E-cadherin expression and a downregulation of N-cadherin, vimentin, and TWIST1 expression, which were involved in the gankyrin/STAT3/Akt pathway [32]. Meloxicam, one of the widely used non-steroidal anti-inflammatory drugs (NSAIDs), reduced the level of overexpressed COX-2 in HCC cells, and subsequently promoted E-cadherin expression and curtailed the expression of MMP-2, leading to a repression of migration and invasion [33]. A monoclonal antibody of the cell surface transmembrane receptor (TM4SF5) was developed to inhibit proliferation in HCC cells accompanied with elevation of E-cadherin expression in vitro, which also suppressed tumor growth in vivo [34]. Huang et al. suggested that antcin K mitigated the metastasis of human HCC cells as characterized by upregulation of E-cadherin and downregulation of MMPs [35]. Recently, matrine was reported to repress the growth of HCC stem cells, which was further clarified by elevation of E-cadherin and fibronectin [36]. In fact, one previous study investigated the inhibitory abilities of 15 matrine derivatives. Among these molecules, compound CH6 suppressed migration of HCC cell lines via stimulation of E-cadherin and inhibition of N-cadherin [37]. The reformed N-trans-feruloyloctopamine (FO) that was originated from garlic skin was revealed to remarkably inhibit the viability and motility of HCC cells in part through upreguation of E-cadherin and downregulation of slug [38]. One group synthesized two kinds of naphthalimide derivatives and indicated that compound 3a ablated cell growth and migration in HCC by promoting the expression of E-cadherin without obvious systemic toxicity at the therapeutic dose [39]. WZ35, a derivative of curcumin, dramatically inhibited metastasis of HCC cells via activation of ROS-dependent JNK pathway with upregulation of E-cadherin and downregulation of MMPs and N-cadherin [40]. Ha et al. recommended that combination regime with sorafenib and vitamin K exerted synergistic effects on inhibition of HCC cell invasion and migration via improvement of E-cadherin expression and suppression of HGF/c-MET signaling pathway [41].

A variety of compounds have been found or designed to resist EMT-mediated metastasis through different molecular mechanisms. For instance, tunicamycin (TM) attenuated cell growth and migration in human HCC cells via inhibition of CD44s- and TGF-α-induced EMT [42]. Furthermore, cordycepin [43] reversed EMT by restoring E-cadherin expression and antagonizing integrin/FAK signaling pathway, while Jianpi Huayu decoction (JHD) [44], nutlin-3 [45] and nemopilema nomurai jellyfish venom (NnV) [46] exhibited antimetastatic properties on HCC cell lines by inhibiting Smad-mediated EMT. One group revealed that casticin hampered EMT of HCC stem cells via reducing the expression of TWIST and N-cadherin, and increasing levels of E-cadherin [25]. Retinoic acid is currently used as a differentiation inducer to improve radioiodide uptake and radiosensitivity of TC [47]. Moreover, Cui et al. demonstrated that all-trans retinoic acid (ATRA) impaired EMT with increased E-cadherin and decreased N-cadherin, and vimentin at transcriptional levels, significantly repressed the growth and metastasis of HCC cells [48]. In addition, arsenic trioxide (As₂O₃), known as the most effective agent for acute paromyelocytic leukemia (APL), also executed a promising antitumor capability on human HCC cells via the demethylation-activated miR-491 [49]. Of note, miR-491 reversed EMT through blockade of NF-κB, transcriptionally upregulating E-cadherin, and downregulating snail, vimentin, and MMP-2 [49]. Gadolinium chloride (GdCl3), which is an injectable MRI contrast agent widely used in the clinic, suppressed EMT on HCC by inducing blockage of tumor associated-macrophages (TAMs) and downregulation of CD206 in TAMs [50]. Scorpion, one of the most important wind calming drugs, suppressed EMT in HCC as verified by upregulation of E-cadherin and downregulation of N-cadherin, and snail [51]. These compounds could be useful for HCC treatment via restoring E-cadherin and reversing EMT.

Pancreatic cancer

PC is known to have a poor prognosis in part due to its high resistance to chemotherapeutic agents. Therefore, new and specific therapeutic strategies are urgently needed. Holy basil leaf extract presented anti-tumorigenic and antimetastatic effects in human PC cells both in vitro and in vivo with upregualtion of E-cadherin [52]. Curcumin reversed TGF-β1-stimulated EMT of PC cells via inhibition of the Hedgehog signaling pathway with an increase in E-cadherin expression level and a decrease in vimentin [53]. Cheng et al. reported that ellagic acid (EA), a polyphenolic compound found in several plants and fruits, suppressed human PC cell growth through reversal of EMT, as evidenced by upregulation of E-cadherin and downregulation of vimentin both in vitro and in vivo [54]. Similarly, one group found that the same dose (40 mg/kg) of EA used by Cheng et al. could inhibit the proliferation of PC in Balb c nude mice [55]. Likewise, embelin was demonstrated to attenuate proliferation and metastasis of human PC in part via repression of EMT by inducing the expression of E-cadherin and reducing the expression of snail, slug, and ZEB1 [56,57]. Furthermore, rottlerin also exerted an inhibitory ability of EMT both in human PC cells and nude mice by restoring E-cadherin expression and mitigating the activity of slug and snail [58]. Yuan et al. provided that α-mangostin was able to thwart the invasion and migration of PC cells through inhibition of ERK signaling pathway, accompanied by upregulation of E-cadherin and downregulation of MMP-2, and MMP-9 [59]. Sanguinarine [60], ursodeoxycholic acid (UDCA) [61], and anthothecol-encapsulated PLGA nanoparticles (Antho-NPs) [62] were suggested to inhibit formation and metastatic properties of PC stem cells via suppression of sonic hedgehog pathway. Notably, the suppressive effect of Antho-NPs was more evident than free anthothecol with the same dose, suggesting that Antho-NPs can be administrated for PC treatment [62]. Furthermore, a significant increase of E-cadherin and a decrease of mesenchymal-related markers such as N-cadherin were corroborated the repression of EMT [60-62]. Propofol, known as an intravenous anesthetic drug, retarded the proliferation and invasion of PC cells by inhibiting the miR-21/slug signaling pathway, leading to upregulation of E-cadherin and slug-dependent PUMA [63]. Galeterone and its analogs exhibited strong antimetastatic effects in PC cells partially through upregulation of E-cadherin and downregulation of N-cadherin, slug and MMPs [64]. One study by Lu et al. had observed that the administration of brusatol could be a potent adjuvant for anticancer therapy in human PC, which was consistent with inhibition of EMT as confirmed by enhancement of E-cadherin expression and decreased expression of vimentin, and TWIST [65]. More importantly, the anticancer effect of brusatol was comparable to some first-line chemotherapeutic agents such as gemcitabine and 5-fluorouracil (5-FU) but with more safe profile. And brusatol exerted a synergistic antitumor function when used together with one of these two agents both in vitro and in vivo. Hexa-D-arginine (D6R), a suppressor of furin, reversed EMT in PC cell lines via regulation of Hippo-YAP signaling pathway [66]. Further, D6R dramatically influenced several key regulatory factors of EMT process with stimulation of E-cadherin expression and downregulation of vimentin, and N-cadherin [66].

Colorectal cancer

CRC is the third most frequent cancer in the Western hemisphere and the incidence is increased with increasing age [67]. Several small compounds that restore E-cadherin expression have been identified to inhibit tumorigenesis and cancer progression in CRC. Cladosporol A, a secondary metabolite from Cladosporium tenuissimum, is considered as a new ligand of PPARγ [68]. Zurlo et al. found that cladosporol A reinforced cell-cell interactions via increasing E-cadherin expression, thereby inhibiting the proliferation in CRC cells [68]. Obatoclax (a pan-inhibitor of the Bcl-2 family), but not ABT-737, recovered E-cadherin expression and resulted in blocking migration and growth of CRC cells [69]. Furthermore, in contrast to ABT-737, obatoclax exhibited its antitumor effects in sublethal doses [69]. Panax notoginseng ethanol extract (PNEE) [70] and cinnamaldehyde (CA) [71] were indicated to enhance the adhesive abilities and simultaneously suppress metastasis in human CRC cells, which were relevant to upregulation of E-cadherin and downregulation of MMPs. In line with this, most recent studies demonstrated that a few natural compounds, such as berberine [72], emodin [73], and novel phytosomal curcumin [74] as well as ethanolic extract of gamboge [75], exhibited inhibitory effects on the growth and metastasis of human CRC through suppression of Wnt/β-catenin signaling pathway, as evidenced by an increase of E-cadherin and concomitant reduction of β-catenin. It was notable that the novel phytosomal curcumin might be more potent than free curcumin in cancer treatment, for the absorption of curcumin was enhanced with application of the former. Furthermore, co-treatment of phytosomal curcumin and 5-FU could significantly reduce the IC50 value of 5-FU [74].

Niclosamide was discovered to block EMT in part via disruption of Axin-GSK3 complex because it succeeded to upsurge E-cadherin amount and reduce the level of snail both in vitro and in vivo [76]. Curcumin was reported to reverse the EMT in colon cancer cells with upregulation of E-cadherin and downregulation of vimentin, and N-cadherin [77]. Notably, co-treatment of curcumin and ulinastatin greatly suppressed hepatic metastases from CRC and significantly extended survival of tumor-bearing mouse models through increased E-cadherin expression and a decrease of MMP-9 expression [78]. Similarly, arctigenin [79] and rosmarinic acid (RA) [80] had been shown to attenuate lung metastasis of CRC via inhibition of EMT in mouse model. Besides, one group showed that the ethanolic extract of bark from Salix aegyptiaca exerted an apparent inhibitory function on EMT of colon cancer cell lines in vitro, which was accompanied by a recovery of E-cadherin levels and a drop of MMPs, snail, and TWIST [81]. Norcantharidin (NCTD), an efficacious anticancer drug that has been used for many years, ablated EMT of colon cancer cells through repression of the αvβ6-ERK-Ets1 signaling pathway [82]. One study suggested that hispidulin, a naturally existing flavonoid, blocked hypoxia-induced EMT in human colon carcinoma cells in part via inhibition of HIF-α expression which was involved in the PTEN/PI3K/Akt pathway [83]. An anthraquinone derivative, physcion, antagonized the migration and invasion dose-dependently and impaired EMT of CRC cells, as manifested by upregulation of E-cadherin and downregulation of N-cadherin and vimentin [84]. Furthermore, numerous plant-derived compounds reversed EMT in human CRC cells through suppressing a series of TGF-β-mediated signaling pathways, containing Pien Tze Huang (PZH) [85,86], resveratrol [87], oxymatrine [88], and JianpiJieDu (JPJD) [89].

Conclusion

In this review article, we summarize the role of E-cadherin in human cancers briefly. We further describe pharmacological small compounds targeting E-cadherin expression for the potential treatment of digestive system cancers. It is well known that EMT is a complex process, which is triggered by numerous factors besides loss of E-cadherin. Therefore, restoring E-cadherin could be not sufficient enough to reverse EMT to MET in human cancer. Targeting multiple EMT inducers may be required to inhibit EMT and tumor metastasis. In addition, although these compounds could upregulate the expression of E-cadherin in digestive system cancers, deeper investigation is necessary to determine whether restoring E-cadherin inhibits tumor metastasis in clinical trials.

Disclosure of conflict of interest

None.