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] |