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INTRODUCTION
Receptor tyrosine kinases (RTKs) are a large family of cell surface receptors, which are transmembrane proteins with intrinsic tyrosine kinase activity. RTKs, upon ligand binding, undergo dimerization and trans-autophosphorylation, which triggers a cascade of intracellular signaling pathways that regulate various cellular processes such as growth, differentiation, metabolism, and apoptosis [1-3].
Axl, a member of the TAM (Tyro3, Axl, Mer) family of RTKs, has been implicated in a variety of pathological conditions, particularly tumorigenesis and metastasis [4,5]. It is a type I transmembrane protein characterized by an extracellular domain comprising two immunoglobulin-like (Ig-like) domains and two fibronectin type III (FNIII) domains, a single transmembrane helix, and an intracellular tyrosine kinase domain [6,7].
The primary ligand for Axl is growth arrest-specific 6 (GAS6), which, upon binding, induces Axl dimerization and autophosphorylation. This activation triggers downstream signaling pathways, including PI3K/Akt, MAPK/ERK, and NF-κB [8], promoting cell survival, proliferation, migration, epithelial-mesenchymal transition (EMT) [9] (a critical step in the metastatic spread of cancer cells), and immune evasion. Axl overexpression and activation have been documented in various malignancies, including, breast cancer, prostate cancer, liver cancer, gastric cancer, non-small cell lung cancer (NSCLC), and acute myeloid leukemia [10,11].
High levels of Axl are often correlated with poor prognosis, increased tumor aggressiveness, and resistance to conventional therapies [12,13]. Additionally, Axl has been found to play a role in the immune system by modulating immune responses, which can have both pro-tumor and anti-tumor effects depending on the context. Its expression is associated with resistance to a variety of cancer therapies, including chemotherapy, targeted therapies, and immunotherapy. This resistance can be attributed to the Axl-mediated activation of survival pathways and changes in the tumor microenvironment that protect cancer cells from therapeutic agents [13]. Given its significant role in cancer progression and acquisition of resistance to treatment, Axl has become an attractive target for the development of novel therapeutic agents.
Although several synthetic Axl inhibitors have been developed and are under investigation [14], there is growing interest in the potential of naturally occurring substances as Axl inhibitors due to their structural diversity, bioactivity, and generally favorable safety profiles. Natural compounds comprising chemical classes such as flavonoids, alkaloids, terpenoids, and saponins are promising bioactive candidates for drug development, characterized by distinctive mechanisms of action. This review aims to provide a comprehensive overview of the current landscape of natural compounds identified as Axl inhibitors, including the mechanisms of action, therapeutic potential, and challenges in clinical applications.
FLAVONOIDS
Flavonoids can be classified into several classless of polyphenolic compounds, including flavones (e.g., apigenin and luteolin), flavonols (e.g., quercetin and kaempferol), isoflavones (e.g., genistein and daidzein), flavanones (e.g., naringenin and hesperetin), flavanols (e.g., catechins), and anthocyanidins (e.g., cyanidin and delphinidin) [15].
They share a common structural backbone consisting of 15 carbon atoms arranged in a C6-C3-C6 configuration, two aromatic rings (A and B) linked by three carbons, and an oxygenated heterocyclic ring (C) (Fig. 1A). The diversity of flavonoids can be further expanded by different modifications such as hydroxylation and glycosylation or oxidation and substitution of the C ring, which result in thousands of compounds found throughout plants. Structural variations in flavonoids affect their biological activities, such as anti-inflammatory, antioxidant, and anticancer properties [16].
Flavones
Apigenin: Apigenin is a flavone derived from fruits, vegetables, herbs, and plant-based beverages, such as grapefruit, parsley, celery, chamomile, and red wine. It has recently gained attention for its potential as an anticancer agent due to its ability to modulate key signaling pathways involved in cancer progression and its low toxicity profile.
This compound has been shown to interfere with cancer cell proliferation, invasion, and metastasis by targeting pathways such as JAK/STAT, PI3K/Akt/mTOR, and NF-κB [17,18]. Additionally, the ability of apigenin to enhance the efficacy of cancer therapies while minimizing side effects underscores its therapeutic potential [19].
Apigenin was observed to reduce both the mRNA and protein levels of Axl in NSCLC cell lines such as A549 and H460 [20] and in the SKOV3 ovarian cancer cell line [21]. This reduction was correlated with a decline in cancer cell proliferation, mediated by the upregulation of p21 and downregulation of X-linked inhibitor of apoptosis protein (XIAP), which could induce cell cycle arrest and apoptosis [20]. Notably, in taxol-resistant SKOV3 cells (SKOV3/TR), the elevated expression of Axl protein was decreased by apigenin, indicating its potential to overcome chemoresistance [21]) (Fig. 1B). These findings suggest that modulation of Axl expression by apigenin might amplify its anti-proliferative and pro-apoptotic effects, presenting a promising strategy for cancer intervention. Furthermore, apigenin could not only downregulate Axl but also influence Tyro3 expression in SKOV3 and SKOV3/TR cells, potentially alleviating the compensatory mechanisms present in taxol-resistant cells [21]. The dual targeting of Axl and Tyro3 by apigenin in cancer cells suggests that it could be highly useful for augmenting the therapeutic effectiveness of chemotherapy and reversing resistance to anticancer drugs.
Luteolin: Luteolin is found in various fruits, vegetables, and herbs, such as celery, parsley, and chamomile. Its chemical structure consists of a flavone backbone with hydroxyl groups at the 3', 4', 5, and 7 positions, specifically described as 3',4',5,7-tetrahydroxyflavone. This configuration contributes to its antioxidant properties, allowing it to neutralize free radicals effectively [22]. Luteolin was observed to reduce the expression of TAM RTKs (Tyro3, Axl, and MerTK) in NSCLC cells, which are associated with oncogenesis, proliferation, survival, and anti-apoptosis, and increase the protein level of p21, a cyclin-dependent kinase inhibitor, leading to growth arrest [23]. In addition, cisplatin-resistant NSCLC cells with elevated levels of Axl remained sensitive to luteolin; thus, it could potentially overcome chemoresistance, possibly by affecting other molecules such as Tyro3 and MerTK, which are also part of the TAM RTK family and contribute to the cytotoxicity of luteolin [23].
Furthermore, luteolin was reported to exhibit antiangiogenic characteristics by disrupting the proliferation, migration, invasion, and tubule formation of human microvascular endothelial cells via modulation of the GAS6/Axl signaling pathway and its corresponding downstream PI3K/Akt/mTOR signaling cascade [24]. These observations imply that luteolin may be used for therapeutic purposes in the management of pathological angiogenesis through incorporation in dietary regimes (Fig. 1B).
Fisetin: Fisetin is a flavone present in many fruits and vegetables, such as strawberries, apples (notably in the skin), persimmons, onions, cucumbers (especially in the skin), and tomatoes, all of which contribute to its potential antioxidant and anti-inflammatory properties [25,26]. It has been shown to effectively inhibit Axl expression in erlotinib-resistant (ER) lung adenocarcinoma cells, specifically HCC827-ER cells [27].
Suppression of Axl by fisetin was found to contribute to the reversal of EMT, evidenced by increased E-cadherin and decreased Snail expression. It was also observed to inactivate the MAPK and AKT pathways, which are crucial for cell survival and proliferation, leading to increased apoptosis and reduced cell viability, especially when combined with erlotinib, indicating synergistic therapeutic efficacy [27]. These findings suggest the potential of fisetin as a therapeutic agent for treating NSCLC cells resistant to erlotinib, offering a strategy for improved patient outcomes (Fig. 1B, Table 1).
Flavonols
Quercetin: Quercetin, a flavonol, contains five hydroxyl groups that contribute to its biological activity and the formation of various derivatives, including glycosides, ethers, sulfates, and prenyl substitutes [28]. It is widely recognized for its considerable health advantages, including pronounced antioxidant, antiviral, antibacterial, anticarcinogenic, and anti-inflammatory activities [29].
Quercetin has been shown to affect Axl expression including Axl-mediated signaling pathways in various cancer cells. In melanoma cell lines (SKMEL-103 and SKMEL-28), it was observed to exert inhibitory effects on Axl expression and its activation, resulting in the perturbation of survival signaling pathways [30]. Notably, compared to SKMEL-28 cells, SKMEL-103 cells exhibited heightened susceptibility to quercetin, which may facilitate an increase in apoptosis and a decrease in cellular viability, thereby positioning quercetin as a compelling candidate for therapeutic intervention in melanoma.
Quercetin was also found to reduce Axl expression in glioblastoma cells (U87MG and U373MG) in a temporally and dose-dependent manner while preserving normal astrocytic counterparts [31]. This attenuation could influence the Axl/IL-6/STAT3 signaling cascade, leading to the inhibition of cell survival, proliferation, migration, and invasive capabilities, thereby highlighting the potential of quercetin as a targeted therapeutic agent for glioblastoma [31].
In a study of NSCLC cells harboring the EGFR C797S mutation, quercetin was observed to downregulate Axl expression at both the transcriptional and posttranslational levels [32]. This reduction resulted in apoptosis and cytotoxicity, indicating that quercetin may effectively overcome resistance to third-generation tyrosine kinase inhibitors (TKIs) while enhancing the responsiveness of cancerous cells to treatment modalities (Fig. 1B).
Kaempferol: Kaempferol is a flavonol with four hydroxyl groups positioned at the 3, 5, 7, and 4' positions on the flavonoid skeleton. It is known for its antioxidant capabilities, which can directly neutralize reactive oxygen species (ROS), such as hydroxyl radicals, superoxide anions, and peroxynitrite [33]. Additionally, it has the ability to chelate iron and copper ions, which serves to inhibit the formation of hydroxyl radicals [34].
Kaempferol was identified as an active compound in Marsdenia tenacissima extract (MTE) with binding affinity for Axl through the formation of five hydrogen bonds, resulting in a significant decrease in Axl phosphorylation and the subsequent dose-dependent inhibition of cell proliferation in NSCLC cells (PC-9 and H1975) [35]. In addition to the direct inhibition of Axl, MTE could also promote endoplasmic reticulum stress (ERS) and immunogenic cell death (ICD), strengthening anticancer immune responses through the enhanced recognition and elimination of tumor cells [35]. By inducing ERS and ICD, kaempferol may serve as a valuable enhancer of immune-mediated cancer therapies, thus potentially augmenting the immune system's effectiveness against malignancies and contributing to the development of superior cancer treatment strategies (Fig. 1B, Table 1).
Flavanols
Catechins: Catechins are classified under a subclass known as flavanols due to the presence of their completely saturated heterocyclic ring (C ring) [36]. They are abundant in dietary products (cocoa and dark chocolate), fruits (apples, grapes, and berries), and beverages (green tea, black tea, and red wine).
Depending on their basic structure, stereoisomeric configurations, and whether they are esterified with gallic acid, catechins can exist in different forms such as (+)-catechin, (-)-epicatechin, (+)-gallocatechin, (-)-epigallocatechin gallate (EGCG), (+)-catechin gallate, and (+)-gallocatechin gallate [36]. Catechins are powerful antioxidants that can neutralize free radicals, reduce oxidative stress, and improve cardiovascular health by lowering blood pressure and enhancing endothelial function [37,38]. They have also been studied for their potential anticancer effects [39].
EGCG was found to suppress both Axl and Tyro3 expression, which was associated with cytotoxic effects in parental and cisplatin-resistant lung cancer cells [40]. These findings indicate that EGCG may reverse cisplatin resistance by targeting Axl expression, suggesting its potential as a therapeutic agent for overcoming chemoresistance. In addition, in human lung cancer cells (H1299), EGCG was identified as the most effective green tea catechin for inhibiting tumor sphere formation.
In a study with spheroid-derived cancer stem cells (H1299-sdCSCs), EGCG inhibited the increased expression of stemness markers (CD133, ALDH1A1, NANOG, SOX2, and OCT4) and EMT-related genes (CDH2, VIM, SNAI, SNAI2, and ZEB1) [41].
Furthermore, EGCG was observed to prevent Axl activation via both GAS6-dependent [40,41] and GAS6-independent pathways [39]. In a mouse xenograft model, EGCG and green tea extract delayed tumor development and reduced tumor size and weight, with lower levels of phosphor-Axl and Axl [41]. These findings suggest that EGCG has potential as an anticancer agent, particularly for interfering with the stemness and tumorigenicity of human lung cancer cells by targeting Axl (Fig. 1B, Table 1).
ALKALOIDS
Alkaloids are a large and complex group of nitrogen-containing secondary metabolites primarily extracted from plants [42]; they not only protect plants from herbivores but also inhibit fungal and bacterial infections, which broadens their use in medicine. Because of their different structures and interactions with biological systems, alkaloids exhibit a variety of pharmacological activities such as antibacterial, antiviral, anticancer, and anti-inflammatory effects [43] and are used for various diseases including cancer, diabetes, and neurological disorders.
Tryptanthrin and its derivatives
Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) is an indole alkaloid found in certain plants and fungi. Recently, tryptanthrin and its derivatives (8-hydroxytryptanthrin and 8-nitrotryptanthrin) were isolated from the culture broth of the mushroom Lepista luscina and were found to inhibit the expression of Axl in A549 human lung adenocarcinoma cells [44]. In particular, tryptanthrin also reduced the expression of immune checkpoint molecules such as PD-L1 and PD-L2 [44]. Given that Axl has been demonstrated to enhance the expression of immune checkpoint molecules, including PD-L1 in lung adenocarcinoma [45], the concurrent downregulation of Axl and immune checkpoint molecules may have significant implications for augmenting the efficacy of cancer treatment by reducing the capacity of cancer cells to evade the immune system (Fig. 2, Table 1).
TERPENOIDS
Terpenoids, also referred to as isoprenoids, are a large and diverse class of natural compounds extracted from various natural sources including plants, animals, microorganisms, insects, and marine organisms [46]. The structural unit of these compounds is the "isoprene" moiety, consisting of five carbon atoms (Fig. 3A). Combinations of two, three, four, and six isoprene units result in the formation of monoterpenes (e.g., carvacrol and paeoniflorin), sesquiterpenes (e.g., artemisinin), diterpenes (e.g., paclitaxel), and triterpenes (e.g., ursolic acid [UA], ganoderic acid A, celastrol, and poricoic acid A), respectively [46] (Fig. 3B).
Terpenoids represent approximately 60% of known natural compounds and are of significant interest owing to their biological and pharmacological properties, including anti-inflammatory, antioxidant, and anticancer properties.
Monoterpenes
Carvacrol: In NSCLC cells (A549 and H460), carvacrol was observed to decrease the levels of Axl mRNA and protein in a dose-dependent manner. Additionally, it effectively blocked the activation of Axl in response to ligand stimulation by GAS6, suggesting that carvacrol is capable of preventing Axl activation [47].
Treatment of NSCLC cells with carvacrol resulted in a dose-dependent decrease in cell proliferation, which was validated by cell viability and clonogenic assays, and suppressed cell migration, as demonstrated by wound healing assay [47]. Taken together, these findings indicate that carvacrol may be a potent anticancer candidate for inhibiting NSCLC cell proliferation and metastasis by targeting Axl (Fig. 3B, Table 1).
Sesquiterpenes
Artemisinin and its derivatives: Artemisinin, a sesquiterpene lactone containing an endoperoxide bridge, is derived from the sweet wormwood plant (Artemisia annua) and has been used to effectively treat malaria, especially drug-resistant strains of Plasmodium falciparum tropicalis.
In addition to antimalarial therapy, artemisinin has been investigated for other therapeutic uses due to its anti-inflammatory, anticancer, and antiparasitic properties. Artemisinin and its active metabolite, dihydroartemisinin (DHA), have been shown to significantly affect Axl expression and signaling in cancer cells, especially in prostate and breast cancer cells [48]. DHA could inhibit Axl expression via regulation of the expression of miR-34a and miR-7, which is partially dependent on chromatin regulation via methylation of histone H3 lysine 27 residues by JARID2 and EZH2 [48].
Inhibition of Axl by DHA could affect downstream signaling pathways, including the Akt/NF-κB pathway, which is important for cancer cell proliferation, migration, and invasion [48] (Fig. 3B). Artesunate, a semisynthetic derivative of artemisinin, was found to exhibit higher cytotoxicity in epithelial than in mesenchymal breast cancer cell lines. In a study of triple-negative breast cancer, a combination of artesunate and the Axl inhibitor TP-0903 synergistically enhanced cytotoxic effects by increasing levels of ROS, DNA damage, and apoptosis in cells (Table 1) [49].
Diterpenes
Yuanhuadine (YD): YD, a daphnane-type diterpene, is the main compound isolated from the flower buds of Daphne genkwa, known as "Yuanhua" in traditional Chinese medicine [50]. In a previous study, YD effectively decreased Axl expression in NSCLC cells, including H292, H292/GR (gefitinib-resistant), H1299, and PC9/GR cells [51]. In particular, YD inhibited cell proliferation in both EGFR-TKI-sensitive and resistant NSCLC cells by degrading Axl and affecting downstream signaling pathways, including those involving phosphorylated Akt and ERK, without altering total protein expression [51].
In vitro experiments demonstrated that YD reduced cell viability in various NSCLC cell lines with low IC50 values, indicating high potency. Additionally, in vivo experiments using xenograft models showed that YD, especially when combined with EGFR-TKIs, significantly inhibited tumor growth [51] (Fig. 3B). Taken together, the ability of YD to degrade Axl and its synergistic effect in combination with EGFR-TKIs suggest that it could be useful in a treatment regimen for NSCLC, especially for patients who have become resistant to standard therapies (Table 1).
Triterpenes
Celastrol: Celastrol is a pentacyclic triterpene extracted from the roots of plants in the Celastraceae family, such as tripterygium wilfordii, tripterygium regelii, and several species of Celastrus [52].
Celastrol was found to have inhibitory effects on Axl protein expression, viability, and clonogenicity in PC-9 cells, including EGFR-mutated cells and gefitinib-resistant cells (PC-9/GR) [53]. When used in combination with gefitinib, celastrol further enhanced the reduction of Axl protein levels. This combination treatment was observed to be more effective than either drug alone in decreasing cell viability and proliferation, as well as in reducing cell migration [53]. These results suggest that the chemoresistance of PC-9/GR cells may be associated with the upregulation of Axl expression, and celastrol may exert its anticancer effects by targeting Axl, thereby increasing the sensitivity of PC-9/GR cells to gefitinib and overcoming their chemoresistance (Fig. 3B).
Corosolic acid (CA): CA is a pentacyclic triterpene found in various species of plants including the leaves of Lagerstroemia speciosa (also known as Banaba), Eriobotrya japonica (Loquat), and Salvia miltiorrhiza [54].
A study reported that CA could affect Axl by downregulating Axl protein levels and inhibiting related signaling pathways, particularly in glioblastoma cells [55]. The study found that CA promoted ubiquitin-mediated proteasomal degradation, which is facilitated by the upregulation of the carboxyl terminus of the Hsc70-interacting protein (CHIP), leading to Axl polyubiquitination. Furthermore, it reduced F-actin protein levels, which interferes with F-actin polymerization, further impairing cell motility and contributing to antimetastatic effects [55].
Molecular docking analysis revealed that CA might directly bind to both GAS6 and Axl, potentially interfering with their interaction and attenuating the Axl-related downstream JAK2/MEK/ERK signaling pathway [55]. Overall, the findings suggest that CA may impair the invasiveness of glioblastoma cells mainly by promoting Axl degradation through CHIP upregulation and inhibiting the GAS6/Axl/JAK axis (Fig. 3B).
Oleanolic acid (OA): OA is a pentacyclic triterpenoid compound present in over 1,600 plant species and particularly abundant in olives (Olea europaea) including olive oil, fruit skins or peels, jujube (Ziziphus jujube), and medicinal herbs such as ginseng (Panax sp.) [56]. Specifically, it is found in high concentrations in the epicuticular waxes of plants, where it acts as a protective barrier against pathogens and water loss.
In a study with gastric cancer cells, OA was found to downregulate Axl expression and inhibit Axl phosphorylation as well as the activation of downstream targets of Axl, such as NF-κB [57]. By targeting Axl, OA exhibited anticancer properties including the reduction of cell viability, proliferation, migration, invasion, and apoptosis [57] (Fig. 3B). Given its potential to modulate Axl, OA may provide anticancer benefits in gastric, esophageal, and other cancers where Axl is overexpressed and overcome drug resistance associated with Axl overexpression.
UA: UA, also known as urson, prunol, and malol, is a pentacyclic triterpenoid compound widely distributed in many plants, berries (e.g., cranberries and bilberries), fruit peels (especially apple peels), and herbs (e.g., rosemary, thyme, oregano, and basil).
In gastric cancer cells, UA was found to inhibit cell proliferation in a dose-dependent manner [58]. In addition, UA treatment resulted in a decrease in phosphorylated Axl (p-Axl) and the p-Axl/Axl ratio, indicating the inhibition of Axl activation. It also effectively blocked the Axl-NF-κB signaling pathway, leading to a reduction in cell migration and the expression of mesenchymal markers and EMT-related transcription factors, including N-cadherin, vimentin, Snail, and Twist [58].
In a gastric cancer xenograft model, UA administration was found to reduce the levels of p-Axl, p-Axl/Axl, and p-IKK α/β [58] (Fig. 3B). Collectively, the findings suggest that the inhibition of Axl signaling by UA may reduce cell proliferation and migration and induce apoptosis in gastric cancer cells through the modulation of the Axl/NF-κB signaling pathway (Table 1).
SAPONINS
Saponins are naturally occurring glycosides present in various plant species, characterized by their soap-like foaming properties when mixed with water. They can be broadly categorized into two main types, i.e., triterpenoid saponins, which are commonly found in legumes, and steroidal saponins, which are prevalent in plants such as yucca and fenugreek.
Saponins exhibit a wide range of biological activities, including antimicrobial and anti-herbivore properties, suggesting roles in plant defense [59]. Additionally, they have significant pharmaceutical properties, such as anti-inflammatory, antifungal, antibacterial, antiparasitic, anticancer, and antiviral activities [59,60].
20(S)-ginsenoside Rh2 (G-Rh2)
G-Rh2, a triterpenoid saponin, is a bioactive compound found in Panax ginseng. A study found that G-Rh2 could directly bind to Axl and inhibit the Axl signaling pathway in colorectal cancer (CRC), leading to several downstream effects including decreased cell proliferation, decreased migration and invasion ability, induction of apoptosis, and G0/G1 phase cell cycle arrest [61].
The silencing of Axl resulted in a notable reduction in the proliferation, migratory capacity, and invasive potential of CRC cells in vitro, as well as a decrease in xenograft tumor proliferation in vivo; conversely, the overexpression of Axl enhanced the proliferation, migration, and invasion of CRC cells [61]. Furthermore, G-Rh2 exhibited a marked inhibitory effect on the growth of CRC xenograft tumors by obstructing Axl signaling [61]. Overall, the results from both in vitro and in vivo experiments highlight the therapeutic potential of G-Rh2, which may target Axl signaling to inhibit CRC progression (Fig. 4, Table 1).
LIGNANS
Lignans are a group of polyphenolic compounds found in a variety of plants, particularly in seeds, grains, and vegetables, where they often play a role in defense against pathogens [62]. These bioactive molecules are classified as phytoestrogens due to their ability to weakly mimic estrogen in the body and have been extensively studied for their potential health benefits, including antioxidant, anticancer, and cardioprotective effects [63,64].
Honokiol (HNK)
HNK is a biphenolic compound that belongs to the class of lignans, phenolic compounds formed by the dimerization of two phenylpropanoid units, and isolated from various species of trees in the genus Magnolia, particularly from the bark, seed cones, and leaves [65].
By downregulating Axl, particularly when combined with rapamycin (RAPA), HNK was found to disrupt pro-tumorigenic signaling pathways, leading to enhanced autophagy and apoptosis in renal cancer cells via modulation of key molecules involved in these processes [66].
Interestingly, in Axl knockout cells, autophagy-related proteins such as Beclin-1 and LC3 were observed to be upregulated, whereas Rubicon, a negative regulator of autophagy, was downregulated [66]. Combination treatment further increased apoptosis and autophagy, indicating that Axl may function as a suppressor of these processes (Fig. 4). Taken together, the findings suggest that targeting Axl can sensitize renal cancer cells to RAPA and HNK, promoting tumor cell death and potentially improving therapeutic outcomes in immunosuppressed patients (Table 1).
STILBENES
Stilbenes are a class of polyphenolic compounds present in a variety of plant species, where they contribute to the plants' defense mechanisms against environmental stressors [67]. An important stilbene, resveratrol, is extensively found in grapes and red wine and is known for its antioxidant, anti-inflammatory, and potential longevity-enhancing properties [68] (Fig. 4).
Other notable stilbenes include pterostilbene, which is abundant in blueberries and known for its improved bioavailability and potential anticancer effects, and piceatannol, which is found in passion fruit and has cardioprotective benefits [69].
Ampelopsins A and C
Ampelopsins A and C, which are oligostilbenes derived from resveratrol, can be found in various plants such as Ampelopsis brevipedunculata var. hancei and Vitis thunbergia.
Both Ampelopsins A and C were reported to induce apoptosis with significant antimetastatic properties in breast cancer cells (MDA-MB-231) [70]. In particular, ampelopsin C was observed to decrease the phosphorylated protein levels of several important kinases, including Axl, Tyro3, EphA2, EphA6, Fyn, Hck, and SRMS, and showed enhanced antiproliferative effects when combined with other compounds such as luteolin and chrysin in MDA-MB-231 cells [70] (Fig. 4, Table 1).
CURCUMINOIDS
Curcuminoids are classified as linear diarylheptanoids, which are a relatively small group of plant secondary metabolites derived from turmeric (Curcuma longa), a flowering plant belonging to the ginger family (Zingiberaceae).
The three main types of curcuminoids are curcumin (diferuloylmethane), demethoxycurcumin (DMC, curcumin II), and bisdemethoxycurcumin (BDMC, curcumin III) [71]. These compounds have been studied for their potential health benefits, including antioxidant, anti-inflammatory, antimicrobial, cardioprotective, neuroprotective, and anticancer effects [72].
Curcumin
Curcumin is the primary bioactive compound found in turmeric. It is a bright yellow chemical that gives turmeric its characteristic color and is responsible for many of its medicinal properties [73].
In a study using NSCLC cells, curcumin was found to decrease Axl expression and inhibit its activation, which has significant implications for cancer cell proliferation [74]. Furthermore, the cytotoxic effects of curcumin were observed in both parental cells and their variants that are resistant to cisplatin and paclitaxel. The effects of curcumin on Axl were associated with the induction of p21, a cyclin-dependent kinase inhibitor, and reduction of XIAP, an anti-apoptotic molecule in both parental and chemoresistant NSCLC cells, indicating that curcumin may be effective in overcoming chemoresistance, potentially through its effects on Axl [74]. These findings suggest that Axl may be a novel target of curcumin, through which it exerts its anticancer activity, offering potential new avenues for cancer treatment strategies.
In breast cancer cells, curcumin was found to target miR-34a, a tumor suppressor microRNA that can downregulate Axl expression, which is associated with the inhibition of EMT [75]. Along with the reduction of Axl expression by curcumin, other EMT-related genes such as the Slug and CD246 genes were also suppressed [75] (Fig. 4). These results indicate that curcumin may downregulate Axl expression, contributing to its anticancer properties via the inhibition of EMT, migration, and invasion (Table 1).
CHALLENGES AND FUTURE DIRECTIONS
Despite the promising potential of natural products as Axl modulators, the current research is predominantly limited to cancer cell line studies, with a notable scarcity of comprehensive in vivo experimental evidence. To optimize the therapeutic efficacy of these compounds, their bioavailability, pharmacokinetics, and pharmacological outcomes must be carefully refined to achieve effective concentrations in vivo. Additionally, the specificity of natural products for Axl versus other drugs needs to be thoroughly investigated to minimize off-target effects.
Detailed studies of the structure-activity relationship can help identify the key structural features responsible for the regulation of Axl and guide the design of more potent and specific molecules. Exploring the synergistic effects of natural Axl inhibitors with conventional therapies or other targeted agents could enhance treatment outcomes.
Rigorous clinical trials are needed to evaluate the safety, efficacy, and pharmacokinetics of natural Axl inhibitors in humans and it is also essential and equally important to explore their pharmacological effects. Further elucidation of the molecular mechanisms underlying Axl inhibition by natural products would provide insights into their therapeutic potential and guide the development of novel therapeutic strategies.
CONCLUSION
Natural products are promising for the development of therapeutic agents for Axl inhibition, offering a diverse array of compounds with potent bioactivity and relatively low toxicity. This review highlights the potential of various natural products, including flavonoids, alkaloids, terpenoids, and polyphenols, for inhibiting Axl and its associated signaling pathways. Continued research in this field holds the potential to uncover novel therapeutic agents for the treatment of Axl-driven diseases, particularly cancer.
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