1. Introduction
The WNT signaling pathway is evolutionarily conserved and holds a critical role in the development of organs and the maintenance of tissue homeostasis [1]. It has been demonstrated that progression, metastasis and resistance to treatment of various cancers can be attributed to the abnormal activation of WNT signaling; therefore, targeting the WNT/β-catenin pathway might be an effective treatment strategy [2,3,4].
Herbal preparations have been employed since ancient times as a fundamental source of therapeutic benefits for various diseases. Small molecules derived from natural products exhibit notable pharmacological activities, including antibacterial, anticancer, antioxidant and antifibrotic properties. Consequently, naturally sourced compounds are frequently utilized to treat diverse diseases, including cancers. Identifying bioactive compounds with significant anticancer activity across numerous plant species may facilitate the development of chemotherapy regimens incorporating these compounds alongside standard chemotherapeutic agents to enhance treatment efficacy and improve patient outcomes. During the last two decades, several natural compounds including curcumin, genistein, resveratrol, vitamin D, epigallocatechin-3-gallate (EGCG), apigenin, baicalin, galangin, silibinin, kaempferol, lycopene, naringenin, artemisinin, quercetin, fisetin, morin, aloe emodin, lupeol, alantolactone and tryptanthrin have been identified as potent modulators of the WNT/β-catenin signaling in various cancer types. Several of them are currently being tested in clinical trials. However, undesirable side effects and the development of resistance significantly restrict their efficacy in clinical applications [5]. There is mounting evidence that natural compounds can regulate the WNT/β-catenin signaling pathway [6]. Nevertheless, their clinical efficacy needs to be determined.
2. Brief Overview of WNT/β-Catenin Signaling Pathway
The WNT signaling pathway can be classified into two distinct pathways, canonical, defined by the intracellular accumulation of β-catenin, and non-canonical (WNT/Ca2+ pathway and planar cell polarity pathway), defined by β-catenin-independent actions [4].
The family of WNT ligands, crucial for stimulating WNT signaling consists of 19 cysteine-rich glycoproteins, each with a molecular weight of about 40 kDa and a length of approximately 350–400 amino acids, sharing a sequence identity of 20–85% [1]. Post-translational modifications, including glycosylation and palmitoylation, mediated by porcupine are essential for their biological activity [7]. Next to WNT ligands, the canonical WNT signaling pathway can also be potentiated by R-spondins (RSPOs), the cysteine-rich glycoproteins that belong to a superfamily of thrombospondin type 1 repeat-containing proteins. RSPO binds to both leucine-rich repeat-containing G-protein-coupled receptor 4/5/6 (LGR4/5/6) and ring finger protein 43/ zinc and ring finger 3 (RNF43/ZNF3) ligases, leading to the clearance of ZNRF3/RNF43 from the plasma membrane [8,9]. RNF43 and its homolog ZNRF3 promote the poly-ubiquitination of lysins in the cytoplasmic sequence of FZDs proteins, inducing endocytosis and the destruction of these receptors at the lysosome [10,11]. Therefore, LGR4/5/6-RSPO-RNF43/ZNF3 interaction results in increased levels of the FZDs on the plasma membrane, leading to increased WNT signaling [8]. Accordingly, in a non-activated state, in the absence of WNTs and RSPOs, ZNRF3 and RNF43 cause FZDs to be internalized and degraded [8].
The WNT/β-catenin signaling pathway is regulated by various antagonists. These antagonists include Dickkopf (DKK) proteins, secreted frizzled-related proteins (sFRPs), WNT inhibitory factor 1 (WIF1), WNT modulator in surface ectoderm (WISE), Kremen (KRM) and Cerberus protein (CER) [12,13,14]. Additionally, the activity of WNTs can be modulated by a highly conserved feedback antagonist, NOTUM, which functions as a deacetylase by removing a palmitate moiety from WNTs, thereby inducing their inactivation. WNT ligands bind to a transmembrane protein called Evenness interrupted/Wntless (EVI/WLS) and are transported through the Golgi apparatus to the plasma membrane [15]. The type of ligand present typically determines the mode of the WNT-signaling network. WNT1, WNT2, WNT3, WNT3A, WNT8a, WNT8b, WNT10a and WNT10b activate the canonical pathway, while WNT4, WNT5A, WNT5B, WNT6, WNT7a, WNT7b and WNT11 activate the non-canonical WNT-signaling pathway [13,16]. In the absence of WNTs, the receptors FZDs and LRP5/6 are located separately on the plasma membrane and the cytosolic β-catenin is captured by a “destruction complex” made up of adenomatous polyposis coli (APC), axis inhibition protein (AXIN), casein kinase 1 (CK1), glycogen synthase kinase 3β (GSK3β) and β-transducin repeat-containing protein (β-TrCP). Phosphorylated β-catenin is then continuously ubiquitinylated by β-TrCP, which leads to its degradation within the proteasome [4]. The activation of the WNT/β-catenin pathway is initiated by the binding of WNT to the FZDs and coreceptors, which are low-density lipoprotein (LDL)-receptor-related proteins 5 and 6 (LRP5 and LRP6). Ten types of FZDs have been identified in mammals (FZD 1–10), each belonging to the “Frizzled class” within the superfamily of G-protein coupled receptors (GPCRs). The N-terminus of FZDs contains a conserved cysteine-rich domain (CRD) with a hydrophobic cavity necessary for binding to the palmitoleate moiety of WNT ligands [17,18]. Upon the binding of the WNT ligand to the FZDs and LRP 5/6, disheveled protein (DVL) is recruited to the cell membrane to provide a platform for AXIN and GSK3β to bind and phosphorylate LRP5/6 (at five conserved PPPSP, also called the PPPSPXS) motifs, thereby preventing the constitutive degradation of β-catenin. As a result of this process, β-catenin becomes stabilized and moves to the nucleus, binds to transcription factors TCF/LEF (T-cell factor/Lymphoid enhancer factor) and recruits activators, such as CREB-binding protein (CBP)/p300, Pygopus (PYGO), B-cell lymphoma 9 (BCL9) and Brahma-related gene-1 (BRG1), leading to the expression of target genes [17,19]. The entry of β-catenin into the nucleus is a major signaling step in the canonical WNT pathway. β-catenin has no identifiable nuclear localization sequence (NLS) and exhibits the non-classical mode of nuclear import [20]. It has been found that the N-terminal, C-terminal tail and Armadillo repeats 10–12 of β-catenin can bind Nup358, Nup62, Nup98 and Nup153 of the nuclear pore complex (NPC), allowing β-catenin to enter into the nucleus through transient interactions [21]. In the nucleus, β-catenin acts as a regulator of gene expression for WNT target genes encoding various proteins that play crucial roles in cellular processes. This includes regulators of proliferation such as vascular endothelial growth factor (VEGF); fibroblast growth factor (FGF); c-JUN; and FOS-related antigen 1 (FRA1), regulators of the canonical WNT pathway such as WNT1-inducible signaling pathway protein 1 (WISP1), AXIN, DKK1, TCF, and LEF1, as well as matrix metalloproteinases and certain components of the extracellular matrix, cadherins, and lineage-specific proteins like microphthalmia-associated transcription factor (MITF) [22].
3. Preclinical and Clinical Studies Evaluating Synthetic Agents as Modulators of WNT/β-Catenin Signaling
In recent decades, novel targeted therapies and immunotherapies have provided great benefits for cancer patients. Nonetheless, the development of resistance limits the success and impedes the curative outcome [23,24]. Therefore, novel therapeutic targets are needed, and modulating WNT/β-catenin signaling is one of the strategies [25]. Aberrant WNT signaling has been implicated in various types of human cancers, contributing to malignant cell transformation, neoplastic proliferation, metastatic dissemination and resistance to treatment [26]. Moreover, the impact of abnormal canonical WNT signaling extends beyond cancer cells, as it significantly interacts with the microenvironment and the immune system dynamically [27]. Prolonged activation of the WNT/β-catenin pathway provides cancer cells with continuous self-renewal and growth and is associated with resistance to therapy [28]. Genetic and epigenetic alterations that affect constituents of WNT/β-catenin signaling pathways are tissue-specific and differ between cancers. Understanding at which level these mutations occur within the pathway is critical to developing new therapeutic strategies [29]. In addition to the common mutations of APC in colorectal cancer and CTNNB1 in hepatocellular carcinoma, dysregulation of various extracellular modulators of WNT signaling (e.g., DKKs, sFRPs, and WIF1) and WNT receptor abundance also plays a role in the development of cancer [28]. Moreover, high expression of vacuolar H+-ATPase (v-ATPase), an electrogenic H+ transporter required for canonical WNT-signaling activation, that triggers abnormal WNT/β-catenin-signaling is observed in prostate, breast, colorectal, pancreatic and ovarian cancer cells [30]. However, the canonical WNT signaling is highly complex and context-dependent in various cancers and high levels of nuclear β-catenin do not always indicate poor prognosis. Therefore, it is necessary to consider the cell type-specific background to understand the cellular outcome of aberrations in WNT-signaling [31]. While detected in benign nevi, nuclear β-catenin is downregulated during melanoma progression [31,32,33]. This contrasts with other cancers, e.g., colorectal cancer [34], hepatocellular carcinoma [35] pancreatic cancer [36], lung cancer [37] or ovarian cancer [38], in which nuclear β-catenin is a driving force of both initiation and progression. Moreover, alterations in WNT/β-catenin signaling have been associated with phenotype switching of melanoma cells, leading to a transition from a highly proliferative/non-invasive state to a slow proliferative/metastatic condition [39]. It has been observed that β-catenin-suppressed invasion occurs through a cell-type specific mechanism involving MITF [31]. On the other hand, activation of β-catenin is crucial for bypassing melanocyte senescence, ultimately leading to melanocyte transformation [40,41], and low efficacy of immunotherapy is observed in melanomas with elevated levels of β-catenin. It has been found that dysregulation of WNT/β-catenin signaling is strongly associated with the biological function of immune cells and immune evasion that play a central role in non-responders or resistant patients receiving immune checkpoint inhibitors (ICIs) [42]. Therefore, the efficacy of ICIs treatment could be significantly improved through combined therapy with molecules targeting the canonical WNT signaling pathway [43]. Furthermore, there is a crosstalk between WNT signaling pathways and other signaling pathways crucial for melanoma development such as MAPK/ERK and phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling. Therefore, considering the role of the WNT/β-catenin pathway in developmental and adult stages and its role in melanoma, the effective and beneficial modulation of the canonical WNT pathway is a challenging task [19]. While targeting the WNT/β-catenin signaling pathway is the subject of a number of clinical trials evaluating drug efficacy in various cancer types (Table 1), studies investigating modulators of WNT/β-catenin pathway in melanoma are still in the preclinical stage with only a limited number of clinical trials. Similarly, in the context of hepatocellular carcinoma, preclinical studies have demonstrated the potential efficacy of small molecules, monoclonal antibodies and plant-derived agents in the regulation of WNT/β-catenin signaling. However, the progression of these therapeutic agents to clinical trial stages remains limited. The clinical advancement of canonical WNT pathway inhibitors for patients with hepatocellular carcinoma faces substantial challenges due to the critical role of WNT/β-catenin signaling in liver homeostasis and regeneration, and its interaction with other signaling pathways [35]. Recent studies have revealed that the activation of PTEN-induced AKT signaling, alongside the suppression of the WNT/β-catenin pathway, is essential for modulating the ratio of LGR5+ cells in liver cancer, suggesting that dual modulation may represent a promising novel approach for the treatment of liver cancer. Additionally, LGR5 has been identified as a significant marker for cancer stem cells (CSCs), highlighting its relevance in cancer research and its prospective applications in therapeutic strategies [44,45].
The canonical WNT pathway can be modulated at various stages, and blocking the production of active WNTs with drugs is one of the strategies. This can be achieved by targeting a key enzyme in WNT biosynthesis, the membrane-bound O-acyltransferase, porcupine. C59 [91] and WNT974 (also known as LGK974) [45,46] are porcupine inhibitors being under investigation in several cancer types, including melanoma. C59, the commercial name of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl) acetamide, synergizes with the anti-CLA-4 antibody in the B16 melanoma model, indicating a possible enhancement in antitumor immunity through a synergistic mechanism [91]. LGK974 is under clinical investigation in melanoma, pancreatic cancer, triple-negative breast cancer, cervical squamous cell cancer, esophageal squamous cell cancer, lung squamous cell cancer (NCT01351103) and BRAF mutant colorectal cancer (NCT01351103 and NCT02278133). Another way of targeting WNT/β-catenin signaling is by affecting the WNT ligands with antibodies, such as WNT-2Ab, a monoclonal antibody with the potential to induce cell death in melanoma cells [92]. WNT-signaling inhibitors can also target FZDs-DVL interaction, e.g., FJ9, which has been found to downregulate WNT/β-catenin signaling and induce apoptosis in lung cancer and melanoma cells [93]. Tankyrases (TNKS and TNKS2) are enzymes that PARylate AXIN1 and AXIN2, resulting in the subsequent ubiquitination and proteasomal degradation of AXIN1/2 [94,95,96]. Tankyrase inhibitors XAV939 [97] and G007-LK [98] represent a promising approach in melanoma therapy. It has been found that G007-LK, can overcome WNT/β-catenin-mediated resistance to immune checkpoint inhibitors [98], whereas nanoparticle formulation for XAV939 (XAV-Np) is efficacious in inhibiting melanoma cell viability, migration and tumor progression in a mouse model of conjunctival melanoma [97]. Blocking the interaction between β-catenin and TCF4 can also act as a novel anticancer strategy [99]. It has been observed that PKF 115–84, a small-molecule inhibitor of β-catenin/TCF/LEF complex downregulated β-catenin expression and β-catenin transcriptional activity, resulting in a dose-dependent reduction in viability of melanoma cells [100]. Moreover, Sinnberg et al. [101] have reported that PKF115–584 decreased melanoma cell migration in vitro and blocked the neural crest migration of melanoma cells in a chick embryo in vivo [101]. Pentoxifylline, a drug approved by the FDA for the treatment of peripheral arterial disease has also been found to inhibit WNT/β-catenin signaling, as it effectively reduced the level of active β-catenin in the nucleus of patient-derived melanoma cells with a high basal expression of β-catenin [102]. Recent studies have also shown that disrupting the interaction between β-catenin and BCL9 can also inhibit oncogenic WNT/β-catenin activity [85,86] and ST316, a novel peptide antagonist of β-catenin that inhibits the interaction with BCL9 and has recently entered the path of clinical trials (NCT05848739) and its activity is investigated in several cancer types including melanoma.
Pharmacological activation of the WNT pathway has also been considered as a potential therapy for melanoma, as riluzole treatment increased WNT/β-catenin signaling to enhance the pigmentation, reduce the proliferation of melanoma cells, and decrease lymph node metastasis in vivo in a mouse melanoma model [103]. Riluzole, an inhibitor of metabotropic glutamate receptor 1 (GRM1) signaling and an FDA-approved drug for amyotrophic lateral sclerosis (ALS) treatment, has been used in an already completed clinical trial (NCT00866840) evaluating riluzole in treating patients with stage III/IV melanoma [90]; its use combined with sorafenib is evaluated in phase I of a clinical trial in patients with advanced solid tumors (NCT01303341). LY2090314, a selective small-molecule inhibitor of GSK3α/β, stabilized β-catenin and stimulated the expression of AXIN2 in A375 melanoma cells, causing a tumor growth delay in vivo both as a single agent and in combination with dacarbazine (DTIC), and induced apoptotic cell death in melanoma cell lines irrespective of the BRAF mutation status [104].
Unfortunately, agents targeting WNT/β-catenin signaling frequently exhibit severe side effects that impair tissue homeostasis and regeneration, and the off-target effects of WNT inhibitors remain an unresolved issue. Natural compounds could be important not only for developing less toxic and more efficient therapeutic strategies when combined with standard anticancer drugs but also for potentiating the efficacy of ICI treatment. This novel treatment approach investigating the therapeutic potential of a combination of vitamin D (as a co-drug) and curcumin (as a supplement) alongside an immunomodulatory cocktail that includes the anti-PD-L1 pembrolizumab in patients with cervical cancer, endometrial carcinoma, or uterine sarcoma has already entered the path of clinical trials (NCT03192059, phase II/completed) [105,106]. It has been revealed some patients derived benefits from the therapy; however, the preclinical effectiveness of the combination of pembrolizumab with a drug cocktail enriched with curcumin followed by radiotherapy did not meet the expectations of clinical activity [105].
4. Characterization of Natural Compounds Modulating the WNT/β-Catenin Pathway in Cancer
Natural products have been employed in traditional medicine across different cultures around the world for a long time. Recently, there has been a resurgence of interest in natural products as alternatives to synthetic medications or complementary therapies to conventional treatments. The historical use and continued investigation of natural products highlight their potential as a valuable tool in the fight against cancer [5]. As the deregulated WNT/β-catenin signaling pathway has been implicated in various cancer types, the identification of natural modulators of this pathway has already attracted considerable attention from the scientific community [43]. Natural compounds have been found to modulate the WNT/β-catenin pathway through different molecular mechanisms, including (1) GSK-3β activation, (2) the inhibition of β-catenin nuclear translocation, (3) the inhibition of β-catenin /TCF interaction, (4) promoting β-catenin protein degradation, (5) the induction of E-cadherin expression, (6) the induction of DKK1 expression, (7) the destabilization of the WNT-FZDs-LRP complex, and others. Moreover, the natural compounds have multiple targets involved in canonical WNT signaling; therefore, the mode of their action depends on the cell type and the state of dysregulation of the WNT/β-catenin pathway in specific diseases [43]. The majority of these therapeutic candidates are still in the preclinical development stage; however, some natural compounds have already entered the path of clinical trials. Preclinical and clinical therapeutic interventions with different natural compounds targeting the WNT/β-catenin signaling pathway in various cancer models are summarized in Table 2 and illustrated in Figure 1.
In the context of the regulation of the canonical WNT signaling pathway in cancer, a variety of natural compounds that belong to flavonoids, anthraquinones, terpenoids, alkaloids and curcuminoids are investigated in preclinical and clinical studies. The following section will focus on the ability of these compounds to modulate the WNT/β-catenin signaling in melanoma and other cancer types.
4.1. Phenolics
4.1.1. Flavonoids
Quercetin
Quercetin [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one] is a natural flavonoid compound that is found abundantly in onions and other dietary sources, including mangoes, grapes, cherries, apples, buckwheat, plums, tomatoes and tea. It possesses multiple pharmacological activities including antioxidant, antiaging, antiviral (including anti-SARS-CoV-2) and anti-inflammatory properties [164,165]. The activity of quercetin has already been evaluated in various cancers, including lung cancer [166], prostate cancer [167], liver cancer [168], breast cancer [169], colon cancer [170], cervical cancer [171], thyroid cancer [151] and melanoma [110]. Numerous studies have shown that its anticancer properties are mediated through various signaling pathways, e.g., p53, nuclear factor-kappa B (NF-κB), MAPK, JAK/STAT, PI3K/AKT and WNT/β-catenin. Apart from regulating these pathways, quercetin also controls the activity of oncogenic and tumor suppressor non-coding RNAs (ncRNAs) [172]. It has been found that quercetin induced apoptosis in melanoma cells and destabilized the WNT-FZD-LRP6 complex by suppressing DVL2 and AXIN2, which resulted in decreased β-catenin and the inhibition of the WNT-responsive gene encoding cyclin D1 (CCND1) and cyclooxygenase (COX2). Moreover, co-treatment with curcumin-induced apoptosis by the downregulation of BCL2 and the induction of caspase 3/7 [110]. The modulation of WNT/β-catenin signaling has also been observed in other cancer types, as quercetin has inhibited the binding between β-catenin TCF [149] and inhibited GSK-3β phosphorylation [150] in colorectal cancer and induced significant anticancer effects against triple-negative breast cancer (TNBC) [171] and thyroid cancer [151] by the increased E-cadherin expression [151,173].
Although quercetin has many health benefits, its oral bioavailability is relatively poor and affected by various factors that limit its application as a clinically therapeutic agent. The water-insoluble nature of quercetin is the most significant reason why it cannot be absorbed into the intestinal tract. Although it can quickly penetrate the phospholipid bilayer of Caco-2 cells due to its hydrophobic properties, it cannot pass through the mucus layer surrounding the gastrointestinal tract, which contains 90% water content. Therefore, various approaches to increase its hydrophilicity, e.g., cyclodextrin inclusion, liposomes, micelles, and nanosuspensions, are investigated [174].
Fisetin
Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a flavonoid abundantly present in a variety of fruits and vegetables, including, apples, strawberries, grapes, persimmon, mangoes, cucumbers, tomatoes, onions, nuts and wine [175,176]. Fisetin offers various pharmacological benefits, including antioxidant, anti-inflammatory, antiangiogenic and anticancer activity [176,177]. Fisetin has been shown to exert anticancer activities, including the inhibition of cell proliferation, angiogenesis, migration, oxidative stress and the induction of apoptosis [177]. It has been found that fisetin exhibits potency against multiple cancer types, including lung [178,179,180], breast [181], prostate [182], colon [183], bladder [184], renal [185], bone [186], pancreatic cancer [187,188], liver [189], oral [190], stomach [191], blood [192], ovarian [193], cervical [194] and melanoma [152,175,176]. These results suggest that fisetin might be a promising therapeutic candidate for cancer treatment. Anticancer properties of fisetin have been ascribed to its involvement in a plethora of signaling pathways, including VEGF, MAPK, NF-κB, PI3K/Akt/mTOR and Nrf2/HO-1, WNT/β-catenin and ERK signaling [176,177]. Syed et al. [152] highlighted the potential of fisetin as a therapeutic option for melanoma treatment via the modulation of the WNT/β-catenin signaling pathway, as the increase in endogenous WNT inhibitors DKK1 and WIF was concomitant with the decrease in the expression of coreceptors FZDs/LRP-6 and DVL has been observed in fisetin-treated melanoma cells. Moreover, the phosphorylation of GSK-3β has been found to be reduced by fisetin, accompanied by a decrease in the stability of β-catenin due to the presence of β-TrCP. As a result, the significant reduction in the protein levels of β-catenin/TCF targets, including c-Myc, BRN2 and MITF has been observed, including in vivo experiments conducted on tumor xenografted mice [152]. Malagoda et al. [195] have reported that high concentrations of fisetin (≥50 µM) decreased the viability of B16F10 melanoma cells, whereas fisetin at lower concentrations (≤20 μM) significantly increased melanin content in mouse melanoma cells and in vivo in a zebrafish larvae model. Based on the results of molecular docking studies, it has been found that fisetin binds to the non-ATP-competitive site of GSK-3β. This leads to the activation of β-catenin signaling, which in turn increases the expression of MITF and tyrosinase in both mRNA and protein levels. This suggests that fisetin promotes melanogenesis by inhibiting GSK-3β and releasing β-catenin [195]. It has also been revealed that fisetin downregulated β-catenin, TCF4 β-catenin target genes, cyclin D1 and matrix metalloproteinase 7 in colon cancer cells [153].
However, administering fisetin can be challenging due to its low water solubility, which limits its biological effects. Therefore, nanoemulsion formulations have been explored to address the issue of delivering fisetin to cancer cells more effectively. Nanoemulsion offers small particle sizes, high drug solubility and loading, good stability, sustained drug release and low toxicity. Another promising way to improve the effectiveness of fisetin is liposome encapsulation, which increases its delivery and absorption [177].
Morin
Morin (3,5,7,2′,4′-pentahydroxyflavone) is a polyphenol compound originally isolated from Moraceae family plants. It can be found in various fruits and vegetables, including mulberries, figs, almonds, onions, osage oranges, tea, coffee, guava leaves, old fustic and apples [196]. In the last decade, this dietary flavanol has received a lot of attention due to its promising pharmacological activities and therapeutic potential. It has been found that morin possesses various beneficial properties such as anti-inflammatory, antioxidant, neuroprotective, antihyperlipidemic, antiviral, antiallergic and anticancer effects [154,196]. Morin has been shown to suppress the proliferation and induce apoptosis in tumor cells, e.g., breast cancer [197], ovarian cancer [198], colorectal cancer [199], hepatocellular carcinoma [200], lung [201], leukemia [202] and melanoma [154,203]. It has been revealed that a morin-induced overexpression of miR-216a in CD133+ melanoma subpopulation inhibited WNT3A expression through miR-216a, which directly targets WNT3A 3′-UTR. Morin treatment significantly reduced the viability of CD133+ melanoma cells and decreased the expression of stemness markers such as CD20, CD133 and CD44. Moreover, morin treatment significantly reduced tumor size in a melanoma xenograft model [154]. Moreover, Lee et al. [203] have reported that morin inhibited melanoma cell growth and promoted apoptosis by downregulating antiapoptotic MCL-1 and BCL-2. This mechanism is partly regulated by the ROS-linked suppression of specificity protein 1 (SP1) expression [203]. However, low aqueous solubility and decreased intestinal absorption significantly limit the therapeutic application of morin. Therefore, various techniques are examined to overcome the low oral bioavailability of morin. Choi et al. [204] proposed a morin-loaded mixed micelle formulation consisting of morin-PluronicF127-Tween80 that significantly increased the bioavailability of morin [204].
4.1.2. Anthraquinones
Aloe Emodin
Aloe emodin (1,8-dihydroxy-3-(hydroxymethyl)-anthraquinone) is a naturally occurring anthraquinone derivative and active ingredient of Chinese herbs, such as Aloe vera, Rheum palmatum L., Cassia occidentalis and Polygonum multiflorum Thunb. Aloe emodin has various pharmacological benefits, including anti-inflammatory, antiviral, antibacterial, hepatoprotective and neuroprotective activity [205]. Moreover, it is a promising anticancer agent that has been investigated in various tumors, including bladder cancer [206], cervical cancer [207], colon cancer [208], gastric cancer [209], melanoma [210], lung cancer [211], liver cancer [212], nasopharyngeal carcinoma [213], oral cancer [214], ovarian cancer [215], prostate cancer [216] and tongue cancer [217]. It has been found that aloe emodin inhibited the viability of A375 and SK-MEL-28 melanoma cells in a dose-dependent manner. Moreover, aloe emodin treatment reduced the migrative and invasive properties of melanoma cells and significantly inhibited the growth of A375 and SK-MEL-28 cells in vivo in a nude mouse transplanted tumor model. Mechanistically, it has been revealed that aloe emodin inhibited the expression levels of WNT3a and p-GSK3-β and promoted β-catenin phosphorylation, leading to the further degradation of β-catenin [155]. Another study has also demonstrated significant antineoplastic and immunomodulatory properties of aloe emodin against M14, SK-MEL-110 and SK-MEL-28 human melanoma cell lines, which was achieved by upregulating the expression of inflammation-associated factors such as interleukin (IL)-2, IL-12, GM-CSF and interferon (IFN)-γ [210]. The antiproliferative efficacy of aloe emodin has also been revealed in androgen-independent DU145 prostate cancer cells, where an aloe emodin treatment resulted in reduced WNT2 and β-catenin mRNA together with decreased β-catenin with their target genes, including cyclin D1 and c-myc [156].
However, the clinical application of aloe emodin is limited due to its hydrophobic character, poor intestinal absorption, short elimination half-life and low bioavailability in vivo [205]. To enhance the water solubility and oral bioavailability of aloe emodin, it was loaded into micelles that markedly enhanced the oral bioavailability of aloe emodin [218].
4.1.3. Curcuminoids
Curcumin
Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione) is a major active component of the spice turmeric (Curcuma longa), a plant related to the ginger family (Zingiberaceae). Curcumin exhibits antibiotic, anti-inflammatory, anti-aging and anticancer activity as suggested by in vitro and in vivo studies and clinical trials [219,220,221,222]. The anticancer activity of curcumin was widely investigated and reported in, e.g., colorectal cancer [110,223], breast cancer [224,225], chronic myeloid leukemia [226], pancreatic cancer [227], glioblastoma [228], ovarian cancer [229], head and neck squamous cell carcinoma [230], bladder cancer [231] and erythroleukemia [232]. The antiproliferative effects observed in vitro and in vivo in various cancer models have prompted the investigation of curcumin’s pharmacological potential in clinical trials. In the past decade, 47 clinical studies have evaluated curcumin’s potential as an antitumor agent, and only a few of them have been completed with results (
To date, clinical trials conducted have demonstrated the safety of curcumin and its derivatives; however, the most commonly reported side effects are mild and predominantly affect the gastrointestinal system [234]. Moreover, various studies have examined the behavior of curcumin in the body, including its distribution, absorption, metabolism and elimination. These studies have found that curcumin is quickly metabolized, poorly absorbed and rapidly eliminated from the body. The lipophilic nature, low stability in aqueous media and low systemic bioavailability of orally administered curcumin are the major drawbacks of its potential use as anticancer drugs [235]. Several delivery systems, such as liposomes, nanoparticles, micelles and phospholipid complexes, have been suggested to enhance the pharmacokinetic properties of curcumin for cancer therapy. For instance, micelles and phospholipid complexes can improve the gastrointestinal absorption of curcumin, resulting in its higher plasma levels [236].
4.2. Terpenoids
4.2.1. Lupeol
Lupeol (3-β)-Lup-20(29)-en-3-ol) (LUP) is a pentacyclic triterpenoid found present in fruits (e.g., strawberries, mangos, red grapes and figs), vegetables (e.g., cucumbers, white cabbage, pepper and tomatoes) and medicinal plants (e.g., licorice and Emblica officinalis) [237]. Lupeol exhibits several pharmacological activities, including anticancer, antioxidant, anti-inflammatory and antimicrobial properties. Various studies have indicated that lupeol has remarkable potential in preventing and treating different types of cancer, including breast cancer [238], oral cancer [239], lung cancer [240], liver cancer [241], osteosarcoma [242], colorectal cancer [243], bladder cancer [244] and melanoma [157,245]. Some studies suggest that lupeol may be effective as a novel therapeutic option for melanoma patients. Bociort et al. [245] revealed that lupeol exhibited dose-dependent cytotoxic activity, induced apoptosis and inhibited cell migration in A375 and RPMI-7951 malignant melanoma cells [245]. The viability of melanoma cell lines exhibiting high WNT/β-catenin activity (Mel 928 and Mel 1241) was significantly diminished after treatment with lupeol, whereas no impact was observed in cells that lacked constitutively active WNT/β-catenin signaling (Mel 1011) [157]. It has been found that the administration of lupeol has produced a dose-dependent reduction in the levels of β-catenin and WNT target genes, namely coding the region determinant-binding protein (CRD-BP), MITF and CCND1, which was in contradiction to Mel 1011 melanoma cells. Furthermore, the administration of lupeol to a nude mouse model with implanted Mel 928 cells demonstrated a substantial reduction in tumor growth and a decreased expression of c-MYC and CCND1. Additionally, immunohistochemical analysis of the tumors revealed a diminished level of nuclear β-catenin in Mel 928-implanted tumors compared to Mel 1011-implanted tumors, where no alteration of β-catenin localization was observed [157]. These findings suggest that treatment with lupeol may have therapeutic potential in reducing tumor growth and suppressing the expression of oncogenes. Lupeol treatment decreased nuclear β-catenin levels in cells with activated WNT/β-catenin signaling while increasing its cytoplasmic levels. This suggests that lupeol may prevent β-catenin from translocating to the nucleus. Furthermore, the efficiency of lupeol was hindered when WNT signaling was suppressed, and no significant decrease in the number of colonies was observed in the colony formation assay [157]. Saleem et al. [246] also highlighted the potential of lupeol as a therapeutic agent for melanoma treatment, as a significant reduction in the viability of 451Lu and WM35 melanoma cells upon treatment with lupeol was obtained. It has been found that lupeol downregulated BCL2 and upregulated BAX, caused cell cycle arrest in the G1-S phase, activated caspase-3 and decreased the expression of cyclin D1, cyclin D2 and CDK2. Moreover, lupeol significantly reduced 451Lu tumor growth in athymic nude mice and modulated the expression of proliferation markers, apoptotic markers and cell cycle regulatory molecules in tumor xenografts [246]. It has also been revealed that lupeol inhibited proliferation and migration, and induced the apoptosis of colorectal cancer cells, which was associated with a decreased expression of β-catenin, TCF4, and β-catenin target genes such as c-Myc and cyclin D1. Moreover, it has been demonstrated that lupeol disturbed stemness in colon cancer cells by regulating Nestin or β-catenin [158]. Similarly, in hepatocellular carcinoma lupeol also induced apoptosis and modulated WNT/β-catenin signaling by the decrease in GSK-3β phosphorylation [159]. It has also been observed that lupeol treatment by targeting β-catenin inhibited the growth of chemoresistant Du145 prostate cancer cells either alone or in combination with Enzalutamide, the second-generation potent androgen receptor antagonist [160].
Despite the therapeutic potential of lupeol, its development as a pharmaceutical drug has been limited by its poor solubility, low bioavailability and inadequate drug delivery [247]. Therefore, numerous approaches have been developed, e.g., lupeol-loaded PEGylated liposomes [248], chitosan-gelatin hydrogel films [249], solid lipid nanoparticles (SLN) [250] and gold nanoparticles [251], to potentiate both the bioavailability and pharmacokinetics of lupeol.
4.2.2. Alantolactone
Alantolactone (ALT) is one of the sesquiterpene lactones (STLs) extracted from Inula helenium L. root (elecampane). It is found in East Asia, Europe and North America. ALT can also be derived from Inula japonica, Aucklandia lappa, Inula racemosa, Inula royleana, Rudbeckia subtomentosa and Radix inulae [252]. It has therapeutic potential for treating various diseases such as asthma, bronchitis, tuberculosis and chronic enterogastritis [252,253]. Moreover, in vitro studies have demonstrated that this compound suppresses the growth of numerous cancer types, including colorectal cancer [254], squamous cell lung cancer [255], gastric cancer [256], pancreatic cancer [257], breast cancer [258] and melanoma [161]. ALT has the potential for cancer treatment as it can effectively reduce inflammation and inhibit tumor growth by regulating abnormal signaling pathways in cancer cells [252,253]. ALT inhibited the viability, migration and invasion of A375 and B16 melanoma cells while promoting their apoptosis [161]. It has been suggested that ALT may have therapeutic potential for treating melanoma by suppressing the WNT/β-catenin signaling pathway, as ALT treatment significantly reduced the expression of β-catenin and its downstream effector c-MYC. Moreover, ALT inhibited GSK3β phosphorylation, and GSK3β has been indicated as a key ALT target in melanoma [161]. ALT has effectively modulated WNT/β-catenin signaling in osteosarcoma by the inhibition of GSK3β phosphorylation and the subsequent reduction in β-catenin. ALT treatment resulted in the apoptosis of osteosarcoma cells and restrained the tumor growth and metastasis of osteosarcoma cells in a xenograft model in vivo. Moreover, the combination of ALT and WNT/β-catenin inhibitor (KYA1197K) resulted in a synergistic effect on inhibiting the proliferation, migration and invasion of osteosarcoma cells [162].
However, due to their low water solubility, the absorption and bioavailability of alantolactone is limited [259]. To improve the bioavailability of ALT, nanostructured carriers have been developed, and micellar nanodrugs could prolong the circulation time [260].
4.3. Alkaloids
Tryptanthrin
Tryptanthrin (indolo [2,1-b] quinazolin-6,12-dione), an indole quinazoline alkaloid, is a naturally occurring chemical compound found in various Chinese medicinal plants, including Strobilanthes cusia, Polygonum tinctorium, Isatis tinctoria [261] and Wrightia tinctoria [262]. This compound has gained significant attention as a promising therapeutic agent due to its structural simplicity, ease of synthesis and diverse range of biological properties (antifungal, antiprotozoal, antioxidant, antimicrobial, anti-inflammatory, antiparasitic, antiallergic) [263]. Moreover, the anticancer activity of tryptanthrin has also been reported in leukemia [264,265], breast cancer [266,267], colorectal adenocarcinoma [268], non-melanoma skin cancer [269] and melanoma [163,262]. Tryptanthrin has been suggested as a therapeutic agent for the treatment of melanoma based on the significant cytotoxicity of tryptanthrin towards A375 melanoma cells, with no effects on normal skin fibroblasts or epithelial cells (HEMA-LP) [163,262]. It has been found that tryptanthrin, the constituent of the most active extract of Wrightia tinctoria leaves, has efficiently downregulated the oncogenic BRAF in A375 cells and the phosphorylation of ERK1/2, and induced by phorbol-12-myristate-13-acetate (PMA) in a concentration-dependent manner. Additionally, tryptanthrin has downregulated β-catenin, completely abolished MITF-M expression [163,262] and inhibited the expression of AKT and NF-κB [260]. In vivo studies on non-obese diabetic severe combined immunodeficiency mice (NOD-SCID) have shown that tryptanthrin (120 mg/kg) treatment resulted in a remarkable reduction in implanted tumor growth [262] and prevented the metastasis of melanoma cells in distant organs in vivo, and a reduction in the metastatic nodules has been observed in lung tissues of a B16F10 tail vein metastasis model [163]. Moreover, it has been observed that tryptanthrin reduced melanoma metastasis and angiogenesis by a decrease in matrix metalloproteinase 9 (MMP-9) and VEGF, respectively [262]. The wound healing assay demonstrated a dose-dependent inhibition of the melanoma cell migration after tryptanthrin treatment. The evaluation of the expression status of β-catenin in melanoma cell lines revealed the accumulation of cytoplasmic β-catenin levels and unaltered nuclear β-catenin levels, suggesting that tryptanthrin can block the nuclear translocation of β-catenin [163]. The clinical use of tryptanthrin is limited by poor solubility and low bioavailability. It has been found that the solubility of tryptanthrin can be improved by encapsulation in nanoparticles, e.g., nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), lipid emulsions (LEs) and polycaprolactone-based nanoparticles (NPs) [270,271].
As demonstrated, natural compounds can affect the canonical WNT signaling pathway in various cancers at various stages, and their mode of action is briefly summarized in Figure 2.
5. Conclusions
A WNT/β-catenin signaling pathway is crucial for cancer growth and progression; thus, targeting this signaling cascade might be an effective treatment strategy. However, the canonical WNT signaling is highly complex and context-dependent in cancers. Therefore, the effective modulation of the WNT pathway in cancers represents a significant challenge and remains an area of active research. Synthetic agents targeting WNT/β-catenin signaling frequently exhibit severe side effects. A variety of natural compounds that belong to flavonoids, anthraquinones, terpenoids, alkaloids, and curcuminoids are investigated in preclinical studies and clinical trials for cancer patients. Their usage is attributed to their health benefits, reduced toxicity and side effects in comparison to synthetic agents. More research is needed to better understand the mechanisms of action of natural compounds, the optimal dosing and absorption, and potential side effects before they can be widely used in clinical practice.
A.G.-M.: writing—original draft; M.C.: review and editing. All authors have read and agreed to the published version of the manuscript.
This is a review and no data were used for the research described in this article.
The authors declare no competing interests.
AKT, protein kinase B signaling; ALT, alantolactone; AML, acute myeloid leukemia; APC, adenomatous polyposis coli; AXIN, axis inhibition protein; BCL9, B-cell lymphoma 9; BRG1, Brahma-related gene-1; CBP, CREB-binding protein; CCND1, cyclin D1; 6-CEPN, 6-C-(E-phenylethenyl)naringenin; CER, Cerberus protein; CK1, casein kinase 1; COX2, cyclooxygenase; CRD-BP, coding region determinant binding protein; CRD, cysteine-rich domain; DKK, Dickkopf; DTIC, dacarbazine; DVL, disheveled protein; EGCG, epigallocatechin-3-gallate; EVI/WLS, Evenness interrupted/Wntless; FGF, fibroblast growth factor; FRA1, FOS-related antigen 1; FZDs, frizzled receptors; GPCRs, G-protein coupled receptors; GRM1, metabotropic glutamate receptor 1; GSK3β, glycogen synthase kinase 3β; HBP1, HMG-box transcription factor 1; HCC, hepatocellular carcinoma, ICIs, immune checkpoint inhibitors; IFN, interferon; IL, interleukin; JMJD2, Jumonji C domain-containing 2; KRM, Kremen; LEs, lipid emulsions; LGR, leucine-rich repeat-containing G-protein-coupled receptor; LRP, lipoprotein receptor-related protein; LUP, lupeol; MITF, microphthalmia-associated transcription factor; MMP-9, matrix metalloproteinase 9; ncRNA, non-coding RNAs; NLCs, nanostructured lipid carriers; NLS, nuclear localization sequence; NPC, nuclear pore complex; NPs, nanoparticles; NSCLC, non-small-cell lung cancer; PI3K, phosphoinositol-3-kinase; PMA, phorbol-12-myristate-13-acetate; PYGO, Pygopus; RNF43, ring finger protein 43; RSPOs, R-spondins; sFRPs, secreted frizzled-related proteins; SLNs, solid lipid nanoparticles; SP1, specificity protein 1; TCF/LEF, T-cell factor/Lymphoid enhancer factor; TNBC, triple-negative breast cancer; TNKS, tankyrase; VEGF, vascular endothelial growth factor; WIF1, WNT inhibitory factor 1; WISE, WNT modulator in surface ectoderm; WISP1, WNT1-inducible-signaling pathway protein 1; ZNF3, zinc and ring finger 3; β-TrCP, β-transducin repeat-containing protein.
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Enlarge this image.Figure 1. The chemical structures of natural compounds targeting WNT/β-catenin signaling in various cancers.
Enlarge this image.Figure 2. Schematic representation of the modulation of WNT/β-catenin signaling pathway by natural compounds in cancers. The nucleus is indicated by a dashed circle, black arrows mark the stimulatory effect and the inhibitory effect is marked by red bar-headed arrows. (* an agent in the clinical trial). ALT, alantolactone, APC, adenomatous polyposis coli; AXIN, axis inhibition protein; BCL9, B-cell lymphoma 9; BRG1, Brahma-related gene-1; CBP, CREB-binding protein; CK1, casein kinase 1; DKK, Dickkopf; DVL, disheveled protein; EGCG, epigallocatechin-3-gallate; EVI/WLS, Evenness interrupted/Wntless; FZD, frizzled; GSK3β, glycogen synthase kinase 3β; LRP, lipoprotein receptor-related protein; Pygo, Pygopus; TCF/LEF, T-cell factor/Lymphoid enhancer factor; Ub; Ubiquitin; WIF1, WNT inhibitory factor 1; β-TrCP, β-transducin repeat-containing protein.
Overview of current and past clinical trials evaluating the activity of synthetic agents targeting WNT pathway in various cancer types (
| Compound | Mechanism of Action/Target | Trial Identifier | Cancer Type | Refs. |
|---|---|---|---|---|
| LGK974 in monotherapy or with PDR001 | porcupine | NCT01351103 | melanoma, TNBC pancreatic cancer, BRAF mutant, | [ |
| LGK974 with LGX818 | NCT02278133 | BRAF-mutant CRC | ||
| ETC-1922159 in monotherapy or with pembrolizumab | porcupine | NCT02521844 | CRC | [ |
| CGX1321 | porcupine | NCT03507998 | BDC, CRC, EC, GAC, GIC, HCC, PDAC | [ |
| CGX1321 in monotherapy or with pembrolizumab or encorafenib + cetuximab) | NCT02675946 | solid tumors, GISTs | [ | |
| RXC004 in monotherapy and with | porcupine | NCT04907851 | advanced solid tumors | [ |
| RXC004 in monotherapy and with nivolumab | NCT03447470 | solid tumors | ||
| NCT04907539 | patients with RNF43 or RSPOs aberrated MSS CRC | |||
| XNW7201 | NCT03901950 | advanced solid | N/A | |
| OMP-131R10 | RSPO inhibitor | NCT02482441 | CRC | [ |
| OMP-18R5 | inhibitors of FZDs | NCT01345201 | solid tumors | [ |
| OMP-18R5 with docetaxel | NCT01957007 | solid tumors | ||
| OMP-18R5 with | NCT02005315 | pancreatic cancer | ||
| OMP-18R5 with paclitaxel | NCT01973309 | BC | [ | |
| OMP-54F28 | FZD8 decoy receptor for WNT ligands | NCT01608867 | solid tumors | [ |
| OMP-54F28 with | NCT02069145 | HCC | ||
| OMP-54F28 with paclitaxel and | NCT02092363 | OC | ||
| OMP-54F28 with | NCT02050178 | pancreatic cancer | ||
| OTSA101 | chimeric | NCT01469975 | SS | [ |
| NCT04176016 | relapsed or refractory SS | |||
| PRI-724 | β-catenin/ | NCT01302405 | CRC | [ |
| PRI-724 with | NCT01764477 | advanced or metastatic PDAC | [ | |
| PRI-724 | NCT01606579 | AML | [ | |
| CWP232291 | β-catenin | NCT03055286 | AML | [ |
| NCT01398462 | AML, CMML | |||
| CWP232291 in monotherapy or with lenalidomide and | NCT02426723 | MM | [ | |
| DKN-01 in monotherapy or with sorafenib | DKK1 | NCT03645980 | HCC | N/A |
| DKN-01 in monotherapy or with atezolizumab | NCT04166721 | metastatic EC | N/A | |
| DKN-01 in monotherapy or with docetaxel | NCT03837353 | PC | [ | |
| DKN-01 | NCT01457417 | MM, solid tumors, | [ | |
| DKN-01 in monotherapy or with paclitaxel | NCT03395080 | endometrial cancer, OC, uterine cancer, carcinosarcoma | [ | |
| DKN-01 in monotherapy or with paclitaxel or | NCT02013154 | EC, GEJA, GOJ, SCC, GAC | [ | |
| DKN-01with | NCT01711671 | MM | N/A | |
| DKN-01 with gemcitabine and cisplatin | NCT02375880 | ICCs, ECCs, CCA | [ | |
| DKN-01 with FOLFIRI/FOLFOX and bevacizumab | NCT05480306 | CRC | [ | |
| DKN-01 with tislelizumab ± CAPOX | NCT04363801 | GC, GAC, GOJ | [ | |
| DKN-01 | NCT04681248 | EC, GEJA, GOJ, SCC, GAC, UC, OC, CS, GC | N/A | |
| DKN-01 in monotherapy or with paclitaxel | NCT03818997 | EC, BTC, GOJ, HPB cancer | N/A | |
| DKN-01 with pembrolizumab | NCT05761951 | endometrial cancer | [ | |
| DKN-01 with nivolumab | NCT04057365 | BTC | N/A | |
| Foxy-5 | WNT5A | NCT02020291 | MBC, mCRC, mPC | [ |
| NCT02655952 | ||||
| NCT03883802 | CRC | |||
| UC-961 | Anti-ROR1 Monoclonal Antibody | NCT02860676 | CLL | [ |
| NCT02222688 | ||||
| NCT02776917 | BC | [ | ||
| UC-961 | NCT03088878 | B-CLL, SLL, MCL, MZL | [ | |
| NCT05431179 | LPDs, LD, NHL | |||
| sulindac | DVL | NCT00245024 | BC | [ |
| NCT04542135 | N/A | |||
| NCT01856322 | CRC | N/A | ||
| NCT00368927 | NSCLC | [ | ||
| NCT00062023 | CRC | N/A | ||
| BNC101 | LGR5 | NCT02726334 | CRC | [ |
| pyrvinium | CK1 | NCT05055323 | PDAC | N/A |
| tegavivint | β-catenin | NCT03459469 | DTs | [ |
| NCT04874480 | recurrent leukemia | N/A | ||
| NCT04851119 | solid tumors | N/A | ||
| tegavivint | NCT04780568 | NSCLC | N/A | |
| E7449 (2X-121) | TNK1/2 | NCT03878849 | OC | [ |
| E7449 in monotherapy or with temozolomide or | NCT01618136 | solid tumors | ||
| ST316 | inhibition of BCL9 and β-catenin interaction | NCT05848739 | BC, pancreatic cancer, NSCLC, SS, CRC, HCC, TNBC, OC | [ |
| niclosamide | FZD1 and BCL-9 inhibition, | NCT02687009 | CRC | [ |
| FZD1 | NCT02519582 | CRC | [ | |
| NCT05188170 | AML | N/A | ||
| niclosamide with | NCT03123978 | mPC, | N/A | |
| NCT02532114 | mPC | [ | ||
| niclosamide with | NCT02807805 | mPC | N/A | |
| riluzole | GRM1 | NCT00866840 | melanoma | [ |
| NCT01303341 | malignant solid neoplasms, recurrent melanoma |
AML, acute myeloid leukemia; B-CLL, B-cell chronic lymphocytic leukemia; BC, breast cancer; BDC, bile duct cancer; BTC, biliary tract cancer; CC, cervical cancer; CCA, cholangiocarcinoma; CLL, chronic lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; CRC, colorectal cancer; CS, carcinosarcoma; DTs, desmoid tumors; EC, esophageal cancer; ECCs, extrahepatic cholangiocarcinomas; ESCC, esophageal squamous-cell carcinomas; GAC, gastric adenocarcinoma; GC, gastric cancer; GEJA, gastroesophageal junction adenocarcinoma; GIC, gastrointestinal cancer; GISTs, gastrointestinal stromal tumors; GOJ, gastrooesophageal junction; GRM1, glutamate receptor 1; HBP1, HMG-box transcription factor 1; HCC, hepatocellular carcinoma; HPB, hepatobiliary; ICCs, intrahepatic cholangiocarcinomas; JMJD2, Jumonji C domain-containing 2; LD, lymphatic disease; LGX818, encorafenib; LPDs, lymphoproliferative disorders; mAb, monoclonal antibody; MBC, metastatic breast cancer; MCL, mantle cell lymphoma; mCRC, Metastatic colorectal cancer; MDS, myelodysplastic syndrome; MM, multiple myeloma; mPC, metastatic prostate cancer; MSS, microsatellite stable; MZL, marginal zone lymphoma; N/A, not available; Nab-P, nab-paclitaxel; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small-cell lung cancer; OC, ovarian cancer; PC, prostate cancer; PDAC, pancreatic adenocarcinoma; PDR001, spartalizumab; RNF43, ring finger protein 43; RSPOs, R-spondins; SCC, squamous cell carcinoma; SLL, small lymphocytic lymphoma; SS, synovial sarcoma; TC, thyroid carcinoma; TNBC, triple-negative breast cancer; UC, uterine cancer.
Overview of clinical trials and preclinical studies evaluating the activity of natural compounds targeting WNT pathway in various cancer types (
| Compound | Natural Sources | Mechanism of | Trial Identifier | Cancer Type | Refs. |
|---|---|---|---|---|---|
| curcumin with | turmeric | β-catenin inhibition | NCT02724202 | CRC | N/A |
| curcumin with | NCT01859858 | [ | |||
| curcumin with | NCT00295035 | [ | |||
| curcumin with | NCT00745134 | CRC | [ | ||
| curcumin | destabilization of the WNT-FZDs-LRP6 complex | preclinical | melanoma | [ | |
| inhibition of β-catenin/DVL | BC | [ | |||
| GSK-3β activation | [ | ||||
| NSCLC, MB | [ | ||||
| suppression of β-catenin, vimentin and N-cadherin, | BC | [ | |||
| suppression of WNT3a, LRP6, β-catenin, C-myc, and survivin | GC | [ | |||
| downregulation of | CRC | [ | |||
| curcumin with | GSK-3β activation | CRC | [ | ||
| curcumin with | β-catenin inhibition | OC | [ | ||
| genistein with FOLFOX or FOLFOX-Avastin | beans, soy, lentils, peas | GSK-3β activation | NCT01985763 | CRC | [ |
| resveratrol | grapes, wine, peanuts, soy | inhibition of | NCT00256334 | CRC | [ |
| SRT501 (micronized resveratrol) | NCT00920803 | [ | |||
| dietary grape-derived low-dose resveratrol | NCT00578396 | CRC | N/A | ||
| vitamin D | mushrooms, fish liver oils, cheese, beef liver, eggs, dark chocolate, milk, yogurt, fat spreads, orange juice, breakfast grains, plant-based beverages | inhibition of | NCT00399607 | colorectal | N/A |
| NCT02603757 | CRC | N/A | |||
| EGCG | cocoa products, tea, pome fruits | GSK-3β activation | preclinical | LC, GC, CRC, | [ |
| upregulation of HBP1 | BC | [ | |||
| apigenin | celery seeds, spinach, parsley, marjoram, Italian oregano, sage, chamomile, | inhibition of | preclinical | CRC | [ |
| lncRNA H19 | HCC | [ | |||
| baicalin | Baikal skullcap, Indian trumpet tree | induction of DKK1 | preclinical | colon cancer | [ |
| inhibition of β-catenin and AXIN2 and stimulation of | osteosarcoma | [ | |||
| suppression of β-catenin nuclear translocation | CC | [ | |||
| β-catenin inhibition | T-ALL | [ | |||
| BC | [ | ||||
| galangin | honey, lesser galangal | β-catenin inhibition | preclinical | CRC, liver cancer | [ |
| galangin with | downregulation of WNT3a and β-catenin | EC | [ | ||
| silibinin | seeds of | suppression of LRP6 | preclinical | PC, BC | [ |
| β-catenin inhibition | CRC | [ | |||
| kaempferol | spinach, kale, dill, chives, | suppression of β-catenin/TCF transcriptional activity | preclinical | CRC | [ |
| reduction in JMJD2C/β-catenin signaling | [ | ||||
| β-catenin inhibition | Rb | [ | |||
| lycopene | tomatoes, apricots, melons, papayas, grapes, peaches, watermelons, | activation of GSK-3β; | preclinical | GC | [ |
| lycopene with quinacrine | reduction in TCF/LEF | BC | [ | ||
| naringenin | grapes, oranges, bergamots, | β-catenin inhibition | preclinical | OC | [ |
| 6-CEPN | β-catenin degradation, | preclinical | HCC | [ | |
| artemisinin | wheat | β-catenin inhibition | preclinical | NSCLC | [ |
| quercetin | onion, asparagus, berries | activation of GSK-3β; | preclinical | CRC, | [ |
| fisetin | strawberry, | activation of DKK1; WIF; GSK-3β; inhibition of | preclinical | melanoma, | [ |
| morin | figs, chestnut, jack fruit, red wine, seaweed, tea, coffee, cereal grains | inhibition of WNT3A | preclinical | melanoma | [ |
| aloe emodin | coffee senna, | inhibition of WNT3a and | preclinical | melanoma | [ |
| reduction in WNT2 and β-catenin mRNA | PC | [ | |||
| lupeol | cabbage, pepper, cucumber, tomato, olive, fig, mango, strawberry, red grapes, American ginseng, shea butter | blocking nuclear β-catenin translocation | preclinical | melanoma | [ |
| inhibition of | colon cancer | [ | |||
| activation of GSK-3β | HCC | [ | |||
| inhibition of β-catenin | PC | [ | |||
| alantolactone | elecampane | activation of GSK-3β | preclinical | melanoma | [ |
| osteosarcoma | [ | ||||
| tryptanthrin | assam indigo, Chinese indigo, woad | inhibition of nuclear β-catenin translocation | preclinical | melanoma | [ |
BC, breast cancer; CC, cervical cancer; CRC, colorectal cancer; EC, esophageal cancer; EGCG, epigallocatechin-3-gallate; GC, gastric cancer; HBP1, HMG-box transcription factor 1; HCC, hepatocellular carcinoma; JMJD2, Jumonji C domain-containing 2; LC, lung cancer; MB, medulloblastoma; N/A, not available; NSCLC, non-small-cell lung cancer; OC, ovarian cancer; PC, prostate cancer; T-ALL, T-cell acute lymphoblastic leukemia; TC, thyroid carcinoma; TNBC, triple-negative breast cancer; 6-CEPN, 6-C-(E-phenylethenyl)naringenin.
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