Small molecules have a long history of acting as drugs for the treatment of hypertension, infections, heart failure, diabetes, asthma, rhinitis, and tumors and comprise approximately 75% of the anticancer drugs approved by the FDA from 1981 to 2014.Recently, many small molecules target EMT and exhibit good therapeutic effects on retarding progressive tissue fibrosis and cancer in experimental conditions.In addition, it is worth noting that many small molecules, such as tivantinib, trametinib, linsitinib, nintedanib, and binimetinib, are in ongoing clinical trials for the treatment of tumors.These cases show promising prospects for treating fibrosis and cancer, which encourages researchers to find effective small molecule drugs for treating fibrosis and cancer. In this review, we describe some important transcription factors, signaling pathways, RNA‐binding proteins and microRNAs and several novel regulators that contribute to EMT and further present some small molecules that exhibit therapeutic effects against EMT. Targeting these mediators with these compounds may be a promising therapeutic strategy to treat fibrosis and cancer.Briefly, histological and pathological analyses show that epithelial cells are present in single cell layers or multilayers and show apical‐basal polarity. Epithelial cells not only interact with the basement membrane with integrins but also communicate with each other via specialized intercellular junctions,round plastic pots including desmosomes, subapical tight junctions, adherens junctions and scattered gap junctions.
These interactions help maintain epithelium integrity and function. However, some stimuli drive EMT in pathological conditions. During the process of EMT, epithelial cell‐cell junctions are dissolved, and the epithelial cells lose their apical‐basal polarity and acquire front‐rear polarity. In addition, the cytoskeletal architecture is reorganized, and E‐cadherin expression is replaced by N‐cadherin expression, which enhances cell motility and invasiveness. In fibrosis, mesenchymal‐like cells transform into myofibroblasts, which can be activated to produce excessive collagen, and in tumors, these mesenchymal‐like cells migrate along with the circulatory system to a secondary location where they form a secondary tumor via mesenchymal‐epithelial transition .It is worth noting that tissue fibrosis and tumors share the common process of EMT, which suggests that targeting EMT may be an effective strategy to treat both fibrosis and tumors . EMT is regulated by various mediators such as transcription factors, signaling pathways, RNA‐binding proteins, and miRNAs. In addition, there are many small molecules that exhibit effective therapeutic effects on tissue fibrosis and tumors by suppressing EMT via targeting these mediators.Snail is a zinc‐finger transcriptional repressor that consists of three isoforms, Snail1, Snail2, and Snail3. Among them, Snail1 and Snail2 are activated in the EMT during development, fibrosis, and cancer. The upregulation of Snail1 is found in many different types of cancer such as gastric, colorectal, and prostate cancer.In addition, the over expression of Snail1 enhanced the motility and invasion of prostate cancer cells, and the silencing of Snail remarkedly suppressed the adhesion, migration, and invasion of Hep‐2 cells.Further study revealed that the knockdown of Snail blocked the EMT, which was accompanied by the down regulation of the expression of MMP‐2, MMP‐9, vimentin, N‐cadherin, and fibronectin.
Moreover, Snail expression was demonstrated at different stages of kidney fibrosis, and the reactivation of Snail‐induced renal fibrosis20 . Furthermore, hypoxia‐inducible factor 1α mediated EMT by regulating Snail and the β‐catenin signaling pathway in early pulmonary fibrosis induced by paraquat.Based on these findings, it was suggested that Snail played a key role in the EMT during fibrosis and cancer, and the targeted inhibition of Snail expression might be an effective therapy to treat fibrosis and tumors.Metformin is a first‐line drug for treating type II diabetes mellitus that has shown a therapeutic effect on many cancers. Further study revealed that metformin increased the expression of E‐cadherin, miR‐200a, miR‐200c, and miR‐429 and decreased the expression of miR‐34a, vimentin, Snail1 and ZEB1 in transforming growth factor‐β ‐induced EMT in the colorectal cancer cell lines SW480 and HCT‐116 .In addition, some compounds derived from natural products have also shown significant intervention in fibrosis and tumors by targeting Snail . Toosendanin, a triterpenoid isolated from Melia toosendan Sieb. et Zucc , isused to prevent and control agricultural pests.Recently, it was reported that toosendanin significantly inhibited TGF‐β1‐induced EMT in lung cancer cells via the extracellular signal‐regulated kinase /Snail pathway and suppressed EMT and tumor growth in pancreatic cancer by deactivating the RAC‐α serine/threonine‐protein kinase /mechanistic target of rapamycin pathway , which suggests that toosendanin is a promising pharmacological agent for the treatment of cancer.A recent study revealed that neferine enhanced oxaliplatin sensitivity by inhibiting EMT via the Snail pathway.In addition, ponicidin is a major diterpenoid compound extracted from Rabdosia rubescens Hara that exhibited a therapeutic effect on TNF‐α‐induced EMT and the metastasis of colorectal cancer by targeting the Akt/glycogen synthase kinase‐3 β /Snail pathway. Moreover, ferulic acid is a bioactive component derived from Ligusticum chuanxiong Hort that suppressed EMT induced by TGF‐β1 via inhibiting the Smad/integrin‐linked kinase/Snail signaling pathway in a renal proximal tubular epithelial cell line , suggesting that ferulic acid might be potent fibrosis antagonist.The two ZEB family members, ZEB1 and ZEB2, are transcriptional inhibitors that are involved in cell proliferation, migration, invasion, and apoptosis.
Extensive studies have confirmed that ZEB1 is upregulated in the EMT and plays a key role in the development of tumors and fibrosis.It was reported that the Np63‐miR‐205 axis increased epithelial marker gene expression and decreased mesenchymal marker gene expression in oral squamous cell carcinoma by down regulating ZEB1 and ZEB2.Moreover, the heterogeneous expression of ZEB1 induced by EMT played an important role in metastasis through the regulation of miR‐200c.In addition, miR‐302a‐3p exerted a protective role via inhibiting ZEB1 and EMT in diabetic kidney disease.These results suggest thatvarious mediators contribute to EMT via the ZEB signaling pathway, suggesting that ZEB is a promising target for the treatment of fibrosis and tumors. Decitabine is a drug used to treat myelodysplastic syndromes that inhibited EMT by regulating the miR‐200/ ZEB signaling pathway in non–small‐cell lung cancer PC9 cells.In addition, a phase Ib/II clinical trial revealed that low‐dose decitabine enhanced the efficacy of immunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer, making it an attractive therapy for cancers.104 Silibinin, a bio-active component from Silybum marianum Gaertn., exhibited anticancer properties in multiple types of cancer, such as bladder and lung cancer . Recent studies revealed that silibinin reversed EMT by inhibiting the expression of ZEB1, vimentin, and MMP‐2 as well as the transactivation of β‐ catenin in bladder cancer metastasis.Furthermore, the combined treatment of silibinin with trichostatin A or decitabine suppressed EMT in non–small‐cell lung cancer.These studies suggest that silibinin is an important candidate anticancer drug. Honokiol was extracted from the seed cones of Magnolia grandiflora L. and showed a therapeutic effect on various cancers. Honokiol effectively inhibited EMT in breast cancer through the STAT3/ZEB1/E‐cadherin axis and reversed EMT in renal cell carcinoma via miR‐141/ZEB2 .STAT3, a member of the STAT protein family, can be phosphorylated as a transcription factor and plays a key role in various cellular processes, including cell growth, apoptosis, and differentiation. Hypoxia is a key mediator that induces EMT during tumor initiation and metastasis, and STAT3 promotes HIF‐1α expression to induce EMT by binding to the promoter of HIF‐1α. In addition, STAT3 was identified as a positive regulator that aggravated TGF‐β1‐induced EMT.In particular, the JAK2/STAT3 signaling pathway had a significant effect on the EMT in multiple cancers. In addition, STAT3 cooperated with other transcription factors promoting EMT, such as Twist and ZEB1.For example, the expression of p‐STAT3 and ZEB1 was positively associated with metastasis, and they cooperatively enhanced EMT in colorectal carcinoma Moreover, STAT3 was upregulated in TGF‐β1‐induced EMT during renal fibrosis, implying that STAT3 is an innovative target for the prevention of fibrosi.Furthermore, there are many mediators that induce EMT through the activation of STAT3, such as Pin1, HOXB8, miR‐30d, and IL‐6.Sepantronium bromide is an inhibitor of survivin that exhibits anticancer properties in multiple cancer types. A recent study revealed that sepantronium bromide reduced the invasion of glioblastoma induced by radiation and reversed EMT by targeting STAT3.Tanshinone IIA is a major bioactive component from the famous medical herb Salvia miltiorrhiza that was reported to attenuate the proliferation of bladder cancer cells . Further study revealed that tanshinone IIA suppressed EMT in bladder cancer cells via the modulation of the STAT3‐CCL2 signaling pathway.In addition,hydroponic bucket tanshinone IIA blocked EMT by regulating the TGF‐β/Smad pathway in peritoneal fibrosis.From these data, it was suggested that compounds that target EMT might have both anti-fibrotic and anticancer properties. In addition, polyphyllin I, a steroidal saponin derived from Paris polyphylla, has shown anti inflammatory and anticancer properties. It was suggested that polyphyllin I, which reversed EMT by modulating the IL‐6/STAT3 pathway, served as a novel solution to conquer EGFR‐TKI resistance in non–small‐cell lung cancer. Therefore, combined treatment with polyphyllin I and erlotinib is a promising therapy for lung cancer patients to strengthen drug efficacy and reduce drug resistance.The other compound, quercetin, is a flavonoid widely distributed in fruits, vegetables, and beverages that shows antioxidative, anti inflammatory, and anticancer properties.
Quercetin reversed IL‐6‐induced EMT in pancreatic cancer cells through STAT3.Collectively, the data indicate that the use of compounds targeting STAT3 might be an effective approach for curing fibrosis and cancer.TGF‐β1 plays a crucial role in various cellular functions, including cell growth, proliferation, differentiation, and apoptosis, and is considered a key mediator in EMT during the processes of tumor formation and fibrosis.Many components contribute to EMT through the TGF‐β1 signaling pathway, which indicates that the inhibition of the TGF‐β1 signaling pathway may be effective in the treatment of cancer and fibrosis. Several excellent reviews have discussed the role of the TGF‐β1 signaling pathway in tumors and fibrosis well. Here, we present several important small molecules that suppress EMT in tumors and fibrosis by targeting the TGF‐β1 signaling pathway . Galunisertib, also known as LY2109761, is a TGF‐β receptor kinase inhibitor that specifically down regulated the phosphorylation of Smad2 and upregulated E‐cadherin expression in cultured human hepatocellular carcinoma cell lines, implying that it could suppress the EMT.Galunisertib is now in ongoing clinical trials in patients with glioblastoma, pancreatic cancer, and hepatocellular carcinoma.Nobiletin is a flavonoid compound isolated from Citrus depressa that suppressed EMT by antagonizing the TGF‐β1/Smad signaling pathway in human non–small‐cell lung cancer cells.In addition, oridonin is a diterpenoid from Rabdosia rubescens Hara that inhibited EMT via blocking TGF‐β1/ Smad2/3 in osteosarcoma.Moreover, GW788388 is a novel inhibitor of TGF‐β type I receptor that inhibited TGF‐β‐ induced EMT and fibrogenesis in db/db mice that showed significant diabetic nephropathy.Furthermore, oxymatrine, a bioactive alkaloid from Sophora japonica L., alleviated EMT induced by high glucose through inhibiting the TGF‐β1/ Smad signaling pathway in NRK‐52E cells, indicating that oxymatrine might be a therapeutic agent for diabetic nephropathy.Isoviolanthin, a flavonoid isolated from Dendrobium officinale Kimura et Migo, suppressed TGF‐β1‐ induced EMT through inhibiting the TGF‐β1/Smad and phosphatidylinositol 3‐kinase /Akt/mTOR signaling pathways in hepatocellular carcinoma cells.In addition, vitamin D, a well‐known inhibitor of EMT, inhibited EMT by negatively regulating the TGF‐β1 signaling pathway in human bronchial epithelial cells, and MART‐10 suppressed metastasis via down regulating EMT in pancreatic cancer cells.The NF‐κB signaling pathway is widely involved in multiple cellular activities, such as cell proliferation, apoptosis, invasion, and inflammation. NF‐κB plays a vital role in the inflammation of tissue fibrosis, and inhibiting NF‐κB activity reduced inflammation and enhanced recovery from CCl4‐induced liver fibrosis.In addition, NF‐κB contributed to inflammation, apoptosis, growth, migration, and invasion of cancer cells.Recently, it was found that the mediator of RNA polymerase II transcription, subunit 28 modulated EMT through NF‐κB in human breast cancer cells, which suggests that the NF‐κB signaling pathway also plays a key role in the process of EMT.Therefore, targeting the NF‐κB signaling pathway may be a good choice to treat fibrosis and tumors. Osthole, a dominant component in Cnidium monnieri Cuss., exhibited various biological activities including neuroprotective, osteogenic, cardiovascular protective, immunomodulatory, hepatoprotective, and antimicrobial effects. Osthole was found to block TGF‐β1‐induced EMT, adhesion, migration, and invasion by the inactivation of the NF‐κB/Snail pathways in A549 cells .In addition, osthole also attenuated insulin‐like growth factor‐ 1‐induced EMT by the PI3K/Akt pathway and inhibited hepatocyte growth factor‐induced EMT via the c‐Met/Akt/ mTOR pathway in human brain cancer cells.Pterostilbene is a stilbene containing in blueberries hat effectivelyblocked the EMT in breast cancer stem cells by the NF‐κB/miR‐488 circuit.Moreover, pterostilbene negatively regulated EMT and inhibited triple‐negative breast cancer metastasis via inducing the expression of miR‐205.