What are the effective inhibitors for treating cancer and fibrosis?---Part 2
Mar 03, 2022
Contact: emily.li@wecistanche.com
Small Molecule Inhibitors Of Epithelial‐mesenchymal Transition For The Treatment Of Cancer And Fibrosis
Ya‐Long Feng1 | Dan‐Qian Chen1 | Nosratola D. Vaziri2 | Yan Guo1,3 |Ying‐Yong Zhao1
Abstract
Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for a targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial‐mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc‐finger E‐box‐binding protein and signal transducer and activator of transcription 3), signaling pathways (transform- ing growth factor‐β1, RAC‐α serine/threonine‐protein kinase, Wnt, nuclear factor‐kappa B, peroxisome proliferator-activated receptor, Notch, and RAS), RNA‐binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.
KEYWORDS: cancer, epithelial‐mesenchymal transition, fibrosis, natural product, small molecule, transcription factor, tumor
Part 2
Cistanche is good for anti-cancer and fibrosis
2.2.4 | Akt signaling pathway
Akt (also known as protein kinase B or Rac) is a serine/threonine‐specific protein kinase that plays a key role in various cellular activities. Many cellular signals are transduced through the Akt signaling pathway, and Akt is involved in EMT in cooperation with other proteins. For example, tripartite motif‐containing 14 is an oncogene that regulated EMT and the metastasis of human gastric cancer by activating Akt signaling.168 M3 muscarinic acetylcholine receptors regulated EMT, perineural invasion, and metastasis in cholangiocarcinoma via the Akt pathway.169 Canopy homolog 2 promoted EMT via activating the Akt/GSK3 pathway in non–small‐cell lung cancer.170 The Akt signaling pathway mediated cigarette‐induced EMT in lung cancer.171 In addition, Akt also promoted EMT cooperation with miRNAs. MiR‐944 inhibited EMT and the metastasis of gastric cancer by the metastasis‐associated colon cancer 1 (MACC1)/Met/Akt signaling pathway.172 MiR‐1296 inhibited EMT and the metastasis of hepatocellular carcinoma via the serine/threonine‐protein kinase 1/PI3K/Akt signaling pathway.173Taken together, these data suggest that Akt plays a key role in EMT cellular signal transduction and that targeting Akt might be an effective approach to treating fibrosis and tumors (Table 1).
Simvastatin is a 3‐hydroxy‐3‐methylglutaryl coenzyme A inhibitor that was originally used to treat cardiovascular diseases. Recently, it was reported that simvastatin had a therapeutic effect in several cancers. The administration of simvastatin suppressed EMT through the phosphatase and tensin homolog (PTEN)/PI3K/Akt pathway in EC9706‐Rcells, suggesting a new therapeutic function for simvastatin in cancers.34 Trichostatin A, a histone deacetylase inhibitor, is an antifungal antibiotic. In addition to its antibiotic properties, trichostatin A alleviated EMT in bleomycin‐induced lung injury in mice via inhibiting the Akt signaling pathwayUbenimex inhibits multiple proteases, including arginyl aminopeptidase, leukotriene A4 hydrolase, alanyl aminopeptidase, and leucyl/cysteinyl aminopeptidase, a membrane dipeptidase used to treat acute myelocytic leukemia and lymphedema. Ubenimex alleviated acquired sorafenib (a first‐line anticancer drug) resistance in renal cell carcinoma via suppressing the Akt pathway.
Luteolin is widely distributed in plants and has shown anti-inflammatory, antioxidant, antimicrobial, and antitumor properties. Luteolin attenuated TGF‐β1‐induced EMT by mediating the PI3K/Akt/NF‐κB‐Snail pathway in lung cancer cells37 (Figure 2). In addition, luteolin attenuated the progression of gastric cancer by reversing EMT via the Notch signaling pathway.38 Moreover, luteolin also suppressed the metastasis of triple‐negative breast cancer via blocking EMT by the downregulation of β‐catenin.174 Furthermore, luteolin suppressed EMT by downregulating the expression of cyclic AMP‐responsive element-binding protein 1175 in colorectal cancer cells.176 Collectively, luteolin showed therapeutic effects in both tissue fibrosis and tumors through various signaling pathways and might be a promising candidate to treat fibrosis and tumors.
α‐Mangostin derived from the pericarp of the mangosteen fruit has been shown to have various cellular functions, such as arresting the cell cycle, inhibiting cell viability, inducing apoptosis, and differentiation, reducing inflammation, and decreasing adhesion. α‐Mangostin suppressed viability and EMT by downregulating the PI3K/Akt pathway in pancreatic cancer.89 Icaritin, a hydrolytic product of icariin that is isolated from members of the epimedium genus, induced the trans‐differentiation of embryonic stem cells into cardiomyocytes, prevented steroid‐associated osteonecrosis and stimulated neuronal differentiation.36 Icaritin inhibited invasion and EMT via targeting the PTEN/Akt/HIF‐1α signaling pathway
2.2.5 | PPARγ signaling pathway
PPAR belongs to the nuclear hormone receptor superfamily and consists of three isoforms including PPARα, PPARβ/δ, and PPARγ. PPAR played essential roles in the regulation of cellular differentiation, development,12 | FENG ET AL.metabolism, and tumorigenesis; in particular, PPARγ exerted a protective role in the development of fibrosis and tumors. A recent study revealed that the activation of PPARγ attenuated cardiac fibrosis, which was mediated by the downregulation of EMT and the TGF‐β/ERK pathway.177 In addition, the overexpression of miR‐130b promoted EMT in glioma cells and human hepatocellular carcinoma, and PPARγ was identified as a functional target of miR‐130b, which was inversely correlated with PPARγ.178 Moreover, it was reported that the PPARγ agonist pioglitazone suppressed fibrotic changes in primary monkey retinal pigment epithelial cells by inhibiting the TGF‐βsignaling pathway.179 Collectively, these results suggest that PPARγ might be a therapeutic target against fibrosis and tumors (Table 1).
Evodiamine from Evodia rutaecarpa (Juss.) Benth. exerts anti-inflammatory, antiobesity, antianxiety, antiallergic, and anticancer effects. Evodiamine suppressed TGF‐β1‐induced EMT in NRK‐52E cells via the PPARγ signaling pathway.53 In addition, curcumin is an active component of Curcuma longa L. that exhibits antioxidant, antibacterial, antifungal, antiviral, anti-inflammatory, antiproliferative, and anticarcinogenic properties. Curcumin had an antifibrotic effect in intestinal fibrosis and prevented the EMT by the PPARγ signaling pathway.
2.2.6 | Notch signaling pathway
As a highly conserved cell signaling system, the Notch signaling pathway is widely involved in cell proliferation and differentiation during embryonic and adult development. Extensive studies have demonstrated that the Notch signaling pathway is also critical for EMT in tumorigenesis and fibrogenesis. The overexpression of Notch1‐induced EMT in PC‐3 cells, and claudin‐1 contributed to EMT by the Notch signaling pathway in human bronchial epithelial cells.180,181 In addition, Notch and TGF‐β1 generated a reciprocal positive regulatory loop and cooperatively regulated EMT in epithelial ovarian cancer cells, which provided new insight into the mechanism of EMT.182Moreover, miR‐34a downregulation induced by hypoxia enhanced EMT via the Notch signaling pathway in tubular epithelial cells, which indicated that the Notch signaling pathway is critical for EMT during fibrosis.66 These cases suggest that a targeted intervention in the Notch signaling pathway might be an effective strategy to treat cancer and fibrosis.
DAPT, a γ‐secretase inhibitor, decreased the expression of Snail and vimentin and increased E‐cadherin expression in two oral squamous cell carcinoma cell lines, Tca8113 and CAL27, indicating that the targeted inhibition of the Notch signaling pathway might be a new therapeutic strategy to treat cancer.183,184 Another γ‐secretase inhibitor, RO4929097, not only inhibited EMT, invasion, and metastasis in cervical cancer HeLa and CaSki cells but also exerted significant therapeutic effects in patients with recurrent malignant glioma, cervical and colon cancer, and advanced solid tumors in clinical trials.67,185,186 3,6‐Dihydroxyflavone is ubiquitous in vegetables and fruits and blocksEMT in breast cancer cells through suppressing the Notch signaling pathway.47 Moreover, luteolin inhibited EMT in gastric cancer by the Notch signaling pathway.38 In addition, emodin is a main bioactive component of Polygonumcuspidatum that suppressed EMT in alveolar epithelial cells via the Notch signaling pathway. Therefore, it is a promising prospect in treating pulmonary fibrosis.96 Furthermore, berberine was isolated from Berberis vulgaris and reversed EMT by blocking the Notch/Snail signaling pathway in mice with diabetic nephropathy.
2.2.7 | RAS signaling pathway
The RAS signaling pathway not only regulates blood pressure and fluid balance but also is involved in many kinds of diseases, including cancer and fibrosis. Recently, emerging evidence has suggested that the RAS signaling pathway plays a key role in EMT during fibrosis and tumorigenesis. Angiotensin II promoted EMT by the interaction between hematopoietic stem cells and the stromal cell‐derived factor‐1/CXR4 axis in intrahepatic cholangiocarcinoma.187 In addition, the overexpression of angiotensin II type 1 receptor-induced EMT and promoted tumorigenesis in human breast cancer cells, and the silencing of angiotensin II type 1 receptor suppressed EMT that was induced by high glucose through inactivating the mTOR/p70s6k signaling pathway in the human proximal tubular epithelial HK‐2FENG ET AL. | 13cell line.188,189 Based on these results, it was suggested that suppressing RAS might be an effective therapy to treat cancer and fibrosis. Losartan is an AT1R antagonist that improved renal fibrosis by suppressing EMT in rats with hyperglycemia. 68Although many RAS inhibitors showed beneficial effects in tumors and fibrosis, few were reported to inhibit EMT in the treatment of cancer and fibrosis.
2.3 | Targeting miRNA signaling pathways by small molecules
MiRNAs are endogenous small non-coding RNAs (19‐25 nucleotides) that bind the 3′‐untranslated region of messenger RNAs to regulate gene expression. Recently, many miRNAs have been found to promote or suppress EMTin fibrosis and tumors. For example, miRNA‐497/Wnt3a/c‐Jun regulated growth and EMT, and miR‐497 served as a tumor suppressor in glioma cells.192 Moreover, miR‐205 inhibited tumor growth, invasion, and EMT via targeting semaphorin 4C in hepatocellular carcinoma.193 Furthermore, the upregulation of miR‐183‐5p induced apoptosis and inhibited EMT, proliferation, invasion, and migration by the downregulation of ezrin in human endometrial cancer cells.194 Collectively, EMT is inhibited by many miRNAs, including miR‐145, miR‐497, miR‐145‐5p, miR‐138,miR‐200a, miR‐200b, miR‐655, miR‐30‐5p, and miR‐32.195-201 In addition, EMT is also promoted by many miRNAs, including miR‐221, miR‐222, miR‐214‐3p, and miR‐181a.
The flavonoids rhamnetin from cloves, berries, and cirsiliol from Cirsium lineare (Thunb.) Sch.‐Bip. showed anti-inflammatory and antitumor properties. Both rhamnetin and cirsiliol induced radio‐sensitization and inhibited EMT by miR‐34a/Notch1 signaling in non–small‐cell lung cancer cells.40 Quercetin alleviated TGF‐β1‐induced fibrosis in HK‐2 cells via downregulating miR‐21 expression and upregulating PTEN and TIMP metallopeptidase inhibitor 3 (TIMP3) expression.45 Sophocarpine from Sophora alopecuroides L. inhibited tumor progression and reversed EMT by targeting miR‐21 in head and neck cancer.51 In addition, sophocarpine exerted a profound antitumor effect through inhibiting EMT induced by TGF‐β.52 Zerumbone from Zingiber zerumbet (L.) Smith exhibited anti‐inflammatory and cancer properties. Recently, it was reported that zerum bone inhibited the theβ‐catenin pathway via miR‐200c to block EMT and cancer stem cells.26 In addition, nicotine upregulated FGFR3 andRB1 and promoted EMT by the downregulation of miR‐99b and miR‐192 in non–small‐cell lung cancer cells.50Moreover, ostiole alleviated EMT‐mediated metastasis by inhibiting miR‐23a‐3p.93 Furthermore, resveratrol inhibited proliferation, invasion, and EMT via the upregulation of miR‐200c in HCT‐116 colorectal cancer cells.
2.4 | Targeting RNA splicing protein signaling pathways by small molecules
RNA‐binding proteins such as RNA‐binding Fox protein 2 (Rbfox2), epithelial splicing regulatory protein 1 (ESRP1), and ESRP2 control the splicing of many gene transcripts and splice nascent RNAs to functionally and structurally different miRNAs to regulate the process of EMT. For example, bleomycin inhibited ESRP1 expression, leading to the increased alternative splicing of FGFR2 to its mesenchymal isoform IIIc, which induced EMT in lung fibrosis.205In addition, overexpressed ESRP1 contributed to EMT in ovarian cancer, inducing a cell‐specific variant of CD44and a protein‐enabled homolog.206 Moreover, Rbfox2 was upregulated during the EMT, and the depletion ofRbfox2 suppressed the expression of mesenchymal marker genes.
Several studies have revealed that small molecules regulate the expression of RNA‐binding proteins to mediate EMT. For example, caffeine, an alkaloid in tea and coffee, reduced p53α expression and upregulated p53βexpression through altering the expression of serine/arginine‐rich splicing factor 3 to regulate EMT
2.5 | Other novel mediators
Here, we present some novel mediators that contribute to EMT with the prospect of treating fibrosis and tumors. N‐acetylglucosaminyltransferase, belonging to the family of glycosyltransferases, played a key role in EMT. Loss of14 | FENG ET AL.N‐acetylglucosaminyltransferase I induced cell‐cell adhesion, decreased cell migration, and suppressed the expression of α‐SMA, vimentin, and N‐cadherin, suggesting the inhibition of EMT.208 Moreover, N‐acetylgluco-aminotransferase I alleviated EMT induced by TGF‐β1 in human MCF‐10A cells.
Protein arginine methyltransferase 1 (PRMT1) mediates many essential cellular functions and plays an important role in cancer cell proliferation. Recent studies revealed that PRMT1 is a novel mediator of EMT, cancer cell migration, and invasion. Twist1 and E‐cadherin are their substrates.210 These findings strongly indicate that targeting PRMT1‐mediated Twist methylation may be a new therapeutic strategy to treat fibrosis and tumors.
Histone H2A type 2‐c (Hist2h2ac) was expressed in all breast cancers, and its expression was induced by EGF in the CD24+/CD29hi/DC44hi cell subpopulation. Hist2h2ac silencing inhibited EGF‐induced ZEB1 expression andE‐cadherin downregulation, which suggested that Hist2h2ac is a novel regulator of EMT in breast cancer.
EGF‐like repeat and discoidin I‐like domain‐containing protein 3 (EDIL3) induced EMT and promoted hepatocellular carcinoma migration, invasion, and angiogenesis in vitro.212 Furthermore, the overexpression of EDIL3induced the activation of ERK and TGF‐β signaling, and the deletion of EDIL3 suppressed EMT in lens epithelial cells through the TGF‐β signaling pathway.213 In addition, the cytoplasmic expression of interleukin‐like EMT inducer (ILEI)is a potential marker of EMT and tumor development in colorectal cancer, and the overexpression of ILEI induced the downregulation of E‐cadherin and the upregulation of vimentin.214 Although the potential of these novel mediators in inducing tissue fibrosis and tumors has been investigated, no study has reported compounds targeting this mediator against fibrosis and tumors. Taken together, these results suggest that these novel mediators play key roles in the EMT, which will provide novel targets for small molecules in antifibrosis and antitumor research in the future.
3 | CONCLUDING COMMENTS
Both tissue fibrosis and tumors lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Mounting studies have demonstrated that EMT plays a critical role in fibrosis and tumors, suggesting that drugs targeting EMT may be an effective therapy against fibrosis and tumors. AlthoughTGF‐β1 is a potent inducer of EMT, new targets are needed due to the controversial role of TGF‐β1, which has been shown to have multiple beneficial roles in various bioactivities. As summarized above, myriad mediators, including many transcription factors (Snail, ZEB, and STAT3), signaling pathways (NF‐κB, Wnt, Akt, and PPAR), RNA‐binding proteins (ESRP1 and ESRP2), and miRNAs, regulate EMT. Targeting these mediators may be a novel therapeutic strategy for antifibrosis and antitumor treatment.
Many small molecules suppress EMT by targeting these mediators, including commercial drugs and compounds derived from natural products. In addition, these compounds that target EMT have shown anticancer effects on multiple types of cancer. For example, luteolin not only attenuated gastric cancer but also showed a therapeutic effect in lung cancer cells. Therefore, we concluded that compounds targeting EMT exerted an anticancer effect in one type of cancer may be effective in other types of cancer. Moreover, curcumin targeted EMT and exhibited both anticancer and antifibrotic properties, which suggests that drugs targeting EMT may exhibit both antifibrotic and anticancer effects. Taken together, these data suggest that drugs targeting EMT not only have both antifibrotic and anticancer effects but also are active against multiple types of organ fibrosis and cancer, which may assist in discovering therapeutic drugs against fibrosis and cancer.
Small molecules are a huge resource for bioactive leading compounds, and it is important to discover novel bioactive compounds effectively and quickly. Here, we summarized several methods to investigate the prospect of natural products as drug candidates. First, molecular docking is used to predict the interaction between a ligand and target protein, and molecular docking‐based virtual screening is helpful to discriminate between active compounds from inactive ones. In addition, during lead optimization, calculations can quickly test modifications to the structures of known active compounds before synthesis. Therefore, computational methodologies can accelerate the discovery of bioactive compounds. Second, reverse pharmacokinetics is used for drug discovery from natural products withFENG ET AL. | 15defined clinical benefits. Reverse pharmacokinetics can be used to guide potential target tissues/organs/molecules, and then further physiologically relevant pharmacological models are designed to discover bioactive compounds and reveal their corresponding mechanisms.
It is worth noting that many compounds show low solubility, which limits their clinical efficiency and restricts their clinical use. Fortunately, there are multiple ways to enhance the bioavailability, such as cocrystallization and the formation of phospholipid complexes and nanoemulsions.
Finally, based on the hypothesis that drugs targeting EMT have both antifibrotic and anticancer effects, many important mediators contributing to EMT have been discovered. Additionally, a great number of compounds suppress EMT in tumors and fibrosis by targeting these mediators. It is hoped that many new drugs are designed and developed in the future based on the aforementioned mediators to treat tumors and fibrosis.
ACKNOWLEDGMENTS
This study was supported by the National Natural Science Foundation of China (Grant Nos. 81673578, 81872985,81603271).
CONFLICT OF INTERESTS
The authors declare that there is no conflict of interest.
AUTHOR CONTRIBUTIONS
All authors were involved in the writing and revision of this manuscript and have provided final approval to submit.
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