Skip to main content
Future Journal of Pharmaceutical Sciences
Download PDF

Receptor tyrosine kinases as a therapeutic target by natural compounds in cancer treatment

Future Journal of Pharmaceutical Sciences volume 7, Article number: 197 (2021) Cite this article

Abstract

Background

Receptor tyrosine kinases (RTKs) are single-pass transmembrane proteins that play significant roles in regulating cellular processes, including cell division and growth. Overexpression and mutations of RTKs have been found in clinical manifestations of different forms of cancer. Therefore, RTKs have received considerable interest as a therapeutic biomarker in the treatment of cancer cells.

Main body of the abstract

Comprehensive data on RTKs, pharmacological and biological properties of natural compounds were systematically searched up to 2021 using relevant keywords from various databases, such as Google Scholar, PubMed, Web of Science, and Scopus. The scientific search by various standard electronic resources and databases unveils the effectiveness of medicinal plants in the treatment of various cancers. In vitro and in vivo studies suggested that bioactive compounds such as flavonoids, phenols, alkaloids, and many others can be used pharmacologically as RTKs inhibitors (RTKI) either by competing with ATP at the ATP binding site of the tyrosine kinase domain or competing for the receptor extracellular domain. Additionally, studies conducted on animal models indicated that inhibition of RTKs catalytic activity by natural compounds is one of the most effective ways to block the activation of RTKs signaling cascades, thereby hampering the proliferation of cancer cells. Furthermore, various pharmacological experiments, transcriptomic, and proteomic data also reported that cancer cells treated with different plants extracts or isolated phytochemicals exhibited better anticancer properties with minimal side effects than synthetic drugs. Clinically, natural compounds have demonstrated significant anti-proliferative effect via induction of cell apoptosis in cancer cell lines.

Short conclusion

An in-depth knowledge of the mechanism of inhibition and structural characterization of RTKs is important to the design of novel and selective RTKIs. This review focuses on the molecular mechanisms and structures of natural compounds RTKI targeting vascular endothelial growth factor, epidermal growth factor receptor, insulin receptor, and platelet-derived growth factor while also giving future directions to ameliorate the scientific burden of cancer.

Graphic abstract

Background

The use of chemotherapeutics has been buoyed by the need to stop rapidly dividing cells in the management of tumors via the activation of apoptotic factors and muddling of the cell cycle, thus inhibiting mitosis. Deject fully, traditional chemotherapy agents lack the required specificity against cancerous cells while also posing a considerable amount of damage on uninfected/beneficial myelocytes or gametocytes [1, 2]

However, this worry has been subdued by the emergence of small molecule kinase inhibitors, characterized by their specificity and selectivity, downregulation of oncogenesis activation proteins, and making their receptor unavailable for binding [3, 4].

As years dwindle, the focus has been shifted on tyrosine kinase as a critical player in tumorigenesis. Specifically, receptor tyrosine kinase (RTK) is a transmembrane receptor upon which dimerization occurs when extracellular signal molecules bind to it [5]. This signal molecule acts as a neurotransmitter, in that they are selective and specific in binding and exhibit no distinct structural variability. Examples include EGF, PDGF, VEGF, etc. [6].

RTK signaling has been cached in the growth and progression of cancerous cells. They activate the growth factors, stimulate cell proliferation, and prevent apoptosis from occurring in cancerous cells [6]. Generation of a phosphorylated cytoplasmic domain tyrosine residue is a recurring theme in RTK activation, thus serving as a communication node during transduction. Binding of small extracellular protein leads to the activation of domain receptor tyrosine kinases which activates the cascades ascribed for cell migration (p53-dependent activation of ERK, PI3K/Akt), upregulating anti-apoptotic cascade (NF-kB & COX-2), Notch1/ Her1 and Hey 2 activation, thus resulting in the metamorphosis into oncogenic cells [7,8,9].

The application of scientific tools, over the years, has allowed an in-depth analysis of the structure and possible mechanism of RTK, bringing about novel therapeutic techniques that could act as kinase inhibitors. Although the positive results have been achieved over time, the development of resistance by cancerous cells is yet to be overcome [10].

Due to the obdurate property of cancerous cells, coupled with the worrisome adverse responses caused by chemotherapeutic agents to the immune system, the use of natural compounds could be the nostrum in overcoming this barrier. Natural compounds such as flavonoids, terpenoids, polyphenols, and alkaloids have increasingly attracted attention as studies have revealed their anticancer, antioxidant, and cardio-protective activity over time. Their ability to modulate ERK, PI3k/Akt cascade, NF-kB activities, and JNK cascades amidst others is entirely plausible [11, 12].

In this study, we deciphered the structure of RTK while explaining its signaling and activation mechanisms. Furthermore, several natural compounds as a therapeutic agent targeting RTK in cancer treatment are accentuated. Novel devices capable of linking structure–biological function activity of natural compounds in a targeted manner are, however, advised to be worked upon.

Main text

Receptor tyrosine kinases

Receptor tyrosine kinases (RTKs) are membrane proteins that aid cell communication with their extracellular milieu, thereby playing a pivotal role in signal transduction, cellular processes, and pathogenesis of different cancer cells. RTKs exist primarily in a single subunit form; however, some such as insulin receptors exist in dimeric form. The structure of RTKs consists of a monomeric transmembrane domain, an extracellular amino (N) terminal composed of ligand binding regions, and an intracellular terminal area flanked by the carboxyl (C) region (13). The hydrophobic part of the transmembrane terminal contains 25 to 38 amino acid residues following active site analysis. The extracellular modules varied considerably in different RTKs subfamily as well as serine/threonine kinases. RTKs are classified on the molecular basis of their natural bound ligand and structural property. Furthermore, the subfamilies of RTKs are characterized by structural diversity of the native conserved elements present at the extracellular region, including immunoglobulin (Ig)-like or epidermal growth factor (EGF)-like domains, fibronectin type III repeats, or cysteine-rich regions. The receptor-ligand complex results in induced conformational change [13, 14].

The major component of the signal transduction pathways is the growth factors, including endothelial growth receptor factor receptor (EGFR), insulin growth factor receptor, fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and insulin-derived growth factor receptor (IGFR). The binding of the growth factor to the extracellular domain activates the RTKs by triggering the receptor dimerization [15]. Clayton et al. [16] reported that binding of IGFR and EGFR induces changes in the dimer and monomer forms of the RTKs, respectively, stimulating cell signaling and RTKs activation. The RTKs can be activated by multiple ligand binding to the extracellular domain. Three of the four human epidermal growth factor receptors (EGFR/HER) receptors, for example, react to a family of ligands generated by 13 genes and splice variants. The mechanism underlying RTKs activation involves phosphorylation of the tyrosine monomer by its neighboring receptor, thereby conducting chemical signals through the plasma membrane [17]. After phosphorylation of the tyrosine kinases, Src homology 2 (SH2) domain and phosphotyrosine binding (PTB) domain active sites for ligands are defined. The mechanism of tyrosine residue phosphorylation at the activated tyrosine kinase domain generates binding sites for phosphotyrosine binding (PTB) and Src homology 2 (SH2) domains. Furthermore, the signal transduction pathways evolved via phosphorylation and activation of SH2 and PTB protein [18].

In a systematic review of RTKs carried out by Metibemu et al. [19], the autoinhibition and activation of RTKs were reported. c-Src, soluble tyrosine kinase, phosphorylate the tyrosine kinase domain at the resting form of RTKs, leading to cell signaling. Thus, phosphorylation helps to prevent autoinhibition by the juxtamembrane domain (Fig. 1). The mutation in the amino acid residues of the juxtamembrane has been linked to the progression of carcinoma cells. The central paradigm of the RTK activation is the phosphorylation of the intracellular tyrosine amino acid residues, forming the basis of cell communication in series of signaling cascades.

Fig. 1
figure 1

Structural representation of the RTKs subfamilies. The extracellular ligand binding region differs across RTKs subfamilies, including immunoglobulin (Ig)-like or epidermal growth factor (EGF)-like domains, fibronectin type III repeats, and cysteine/leucine-rich regions. The single-pass transmembrane is linked to the intracellular tyrosine kinase domain (TKD) by the juxtamembrane. When extracellular ligands or a growth factor binds to the extracellular domain, it stimulates dimerization with neighboring RTKs. Dimerization leads to activation of the catalytic site within the TKD. Thus, autophosphorylation occurs as the receptor becomes activated [19]

Full size image

Vascular endothelial growth factor receptor

Vascular endothelial growth factor receptor (VEGFR), formerly known as vascular permeability factor, is synthesized by the fibroblast involved in angiogenesis and vasculogenesis [20]. VEGF denotes the subfamily and structural-related VEGF polypeptides. VEGFRs activate signal transduction pathways through three structural analogs of VEGFs: VEGFR1 (Flt-1) expressed in macrophages and monocytes, VEGFR2 (KDR/Flk-1), and VEGFR3 (Flt4) found in endothelial cells of vascular tissues and lymphocytes [21]. The VEGF family can be classified into five growth factors VEGFA (the prototype, also known as VEGFA165), VEGFB, VEGFC, VEGF-D, and placenta growth factor (PlGF). Although the VEGF family has been reported to be homodimeric polypeptides, heterodimer forms of VEGF and PIGF have been reported naturally [22]. The family of VEGF performs diverse functions. VEGF A is primarily involved in blood vessels and lymphangiogenesis while binding to the first receptor of VEGFs. VEGFs also function in the regulation of vasodilation through an indirect release of nitric acid [23]. The mechanism of VEGF A in the homeostatic regulation of vasodilation is not yet known. VEGF B and C control the embryonic formation of the circulatory system and lymphatic vessel formation. VEGF D, also called c-fos-induced growth factor, is a glycoprotein involved in stimulating lymphangiogenesis and potential endothelial cell growth and survival. VEGF C and D binds specifically to VEGF receptor 3 [21, 24].

The VEGFs have numerous clinical applications; for example, overexpression of VEGF A has been studied in breast cancer prognosis and damage to blood vessels in the central nervous system [25]. Stacker and Achen [26] reported that VEGF D had been used as a diagnostic biomarker in rare hereditary diseases such as angiosarcoma and lymphangioleiomyomatosis.

Epidermal growth factor receptor

The epidermal growth factor is a tyrosine (EGFR) kinase that plays a crucial role in the proliferation of tumor cells. It is a transmembrane protein that belongs to the ErbB family of receptors overexpressed in different cancer carcinomas. EGFR is composed of four members that are similar in structure and cellular functions: ErbB1 (EGFR or HER1), ErbB2 (HER2), ErbB3.

(HER3) and ErbB4 (HER4) [27]. According to phylogenetic studies, the human epithelial receptor consists of 11 species and is classified based on binding to the four EGFR members, including transforming growth factor α that binds to HER1, epidermal regulators that bind to both HER1/HER4 and Neuregulin that binds HER3 and HER4 [28]. The phosphorylation of downflows is mediated by signaling protein and catalyzes series of signaling cascades including PI3K– PTEN–AKT, MAPK, ERK, and JAK/ STAT pathways, thereby inducing tumor cells, DNA synthesis, and angiogenesis [29].

The structural characterization of HER in oncogene has led to novel therapeutic agents against different cancer cells, including lung and colon cancer. The first generation inhibitors of EGFR are erlotinib and gefitinib. Afatinib and osimertinib are the second and third generations of EGFR inhibitors [30]. Immunotherapy has also proved to be potent inhibitors of EGFR by developing monoclonal antibodies, notably Cetuximab [31]. Jorissen et al. [32] investigated the mechanism involved in ligand-receptor binding and the complex system of the signaling pathways. Thus, abnormal activation of EGFR, including Shc, Ras/MAPK pathway, JAKs, and STATs pathways, has several pathophysiology-related diseases, particularly cancer cell proliferation [33].

Platelet-derived growth factor receptor

Platelet-derived growth factor receptor (PDGFR) is tyrosine kinases, and it encodes four platelet-derived growth factor (PDGF) genes (PDGFA, PDGFB, PDGFC, and PDGFD) that have been mapped out genetically on different chromosomes locations in humans and mice [34]. PDGF is a dimer with a disulfide linkage to A and B polypeptide chains. The receptor of the PDGF can exist in two isoforms, either as a homodimer (PDGF-AA, PDGF-BB) or heterodimer (PDGF-AB) in a ligand-dependent manner. The intracellular region and the extracellular site contain a tyrosine kinase domain and five immunoglobulin-like domains [35]. According to Shen et al. [36], cellular functions, including embryogenesis, cell division, and inflammation, stimulate PDGF binding to their respective receptors. Furthermore, PDGF has been found predominantly in smooth muscle cells, connectives tissues, astrocytes, fibroblast, and keratinocytes and, to a large extent, brain neurons, kidney, and mammary endothelial cells [19, 35]. In a study carried out by Andrae et al. [37], the expression of PDGF is downregulated by the following signaling pathways, STAT Ras/mitogen-activated protein kinase (MAPK), PI-3 kinase, and phospholipase-γ (PLCγ) pathways. Because of the PGDF's pivotal role in developing tumor cells, one of the most effective ways to halt PGDF signaling is to inhibit the ATP competitive tyrosine kinase domain [37]. There has been no specificity in the mechanism of action of the available PDGFR inhibitors, including imatinib, nilotinib, and sunitinib, although they have been reported to be effective in disrupting the signaling cascades. Inhibition of PDGFR by small molecules or natural products has not gained much attention; however, immunological techniques in blocking PGDF signaling have been developed [13, 17].

Insulin receptors

The insulin receptor is a transmembrane protein that plays a vital role in the biochemical metabolism of carbohydrate, lipid, protein, and its abnormal regulations can cause various clinical diseases, including cancer and diabetes mellitus. It is a polypeptide hormone that is produced in the β-cell of the pancreas [38]. Insulin has been of the most extensively studied protein because of its therapeutic role in treating diabetic patients, and it is the first protein to have its primary amino acid structure sequenced. Several biophysical techniques, including cryo-electron microscope, have been utilized to elucidate the structure of the insulin receptor [39]. Scapin et al. [40] carried out the structural characterization of the insulin receptor complex using a high resolution of single-particle CryoEM analysis. The insulin receptor consists of an α and β chain, which exist in their heterodimer forms and is found at the exterior of the plasma membrane. The amino terminal of the β-chain contains three regions: tyrosine ATP-dependent kinase, transmembrane terminal, and a juxtamembrane. The activation of insulin receptors occurs through insulin growth factor analogs' binding, the disulfide-rich IGF-1 and IGF-2 [41]. IR autophosphorylates the insulin receptor substrate (IRS), driving the activation of signaling pathways, including ERK/PI-3-K/RAS/MEK/ pathways [42].

Natural compounds as RTKs inhibitors

Natural compounds have been utilized in folklore medicine, pharmaceutical sciences, and many other related medical fields since time immemorial in treating several diseases, including neurodegenerative disease, cancer, diabetes, and inflammations. They are categorized into various classes (Fig. 2) and their therapeutic potential has been studied and documented in several continents such as Asia, Europe, and Africa [43]. Many well-known drug candidates are derived from plants. For example, Artemisinin isolated from the bark of Artemisia annua has been influential in the treatment of malaria. Also, the anticancer drugs: Paclitaxel, docetaxel, Cabazitaxel are plant-based derived compounds used to treat different cancer cell lines [44]. Fidyt et al. [45] have reported the anticancer property of the β-caryophyllene, a natural compound in the family of sesquiterpene. The mechanism of action of natural compounds on different signaling pathways and how it induces cell death in various metabolic diseases have been studied extensively [46] (Fig. 3).

Fig. 2
figure 2

Classification of phytochemicals

Full size image
Fig. 3
figure 3

Inhibition of signal transduction pathways by natural compounds [47]

Full size image

Flavonoids

Flavonoids are secondary phytochemicals derived from dietary sources such as fruits, grains, tea, wine, and vegetables. Flavonoids are grouped into seven: flavanones, flavones, isoflavones, flavanols, flavonols, flavanolones, and anthocyanins. The chemical structure of flavonoids contains a 15-carbon backbone with two benzene rings linked together by a heterocyclic oxygen-embedded ring [47]. Substitution reactions, including hydroxylation, methoxylation, and glycosylation in the subclass of flavonoids (Fig. 4), have led to their diversity. Although flavonoids are poorly absorbed and rapidly metabolized representing a low bioavailability rate, they have demonstrated various biological functions, mainly antioxidant, metal chelators, anticancer, and anti-inflammatory agents [48].

Fig. 4
figure 4

Chemical structure of selected flavonoids

Full size image

Quercetin is a glycoside chemically known as 3,3′,4′,5,7‐ pentahydroxyflavone (C15H10O7) and one of the most ubiquitous polyphenolic flavonoids present in fruits and vegetables. Quercetin and its derivatives have been helpful in the treatment of cancer, allergies, inflammation, and viral diseases [49]. Zheng et al. [50] investigated that the anti-metastatic and anticancer effect of quercetin against various tumor cells such as leukemia, lung and colon cancer, and breast cancer may be due to its inhibitory potential on enzyme-catalyzed reaction involved in carcinogenesis. Quercetin induced cell cycle arrest at G1 phase and apoptosis in human breast cancer MDA-MB-453 cells in a dose and time-dependent manner. Furthermore, quercetin inhibits cellular growth significantly during the G2 phase in breast cancer MCF-7 cells through a time and concentration-dependent manner [51].

VEGFR-1 and VEGFR-2 are fundamental in the formation of the angiogenesis process by regulating cell growth and proliferation. In a study conducted by Zhao et al. [52], quercetin selectively inhibits VEGFR-2 mRNA with maximum effect at a concentration of 100 and 200 µm. The anti-angiogenic activity of quercetin has also been expressed in the downregulation of signaling pathways of VEGFR-2, ERK, and p38MAPK. However, further in vivo studies are required to establish quercetin angiogenic property [53, 54]. Sun et al. [55] reported the molecular mechanism underlying the combined effect of quercetin and metformin in cancer cells. The result shows that co-treatment of quercetin and metformin triggers apoptosis by inhibiting the VEGF/Akt/PI3K pathway in prostate cancer cells. Quercetin has also proven to be effective as combined chemotherapy with irinotecan to treat gastric cancer cells by blocking growth factor receptors [53]. Furthermore, Donnini et al. [56] demonstrated the various angiogenic effect of quercetin and its structural analog, quercetin-3-o-glucoside, on VEGF-activated endothelial cells.

EGFR signaling pathway plays a significant role in the progression of metastatic prostate cancer, making it a novel target in various cancer cells. Quercetin blocks prostate cancer cell growth through the EGF receptor by homeostatic regulation of several cell adhesion molecules, including vimentin, E-cadherin, and N-cadherin [57]. Previous studies show that quercetin and quercetin 3-O-glucoside downregulate the expression of EGFR in a cirrhotic animal model, pancreatic tumor cells, and EGFR-mediated signaling pathway [58].

Recent studies demonstrated that quercetin and silibinin could disrupt cell growth in prostate cancer cells by inhibiting the IGF-I and IGFBP-3 through apoptotic cell death in G and S phases [59]. Additionally, quercetin-3-O-glucoside, a bioactive metabolite of quercetin, inhibits PDGF in vascular smooth muscle cells [60]. Huang et al. [61] evident that quercetin is a potent anticancer agent against human oral cancer cells by activating the FOXO1 transcription factor via G2 cell arrest caused by DNA damage. Fan et al. [62] investigated the anticancer effect of dietary flavonoids on cancer cells. Luteolin and quercetin show promising anticancer agents through reduction of Src/Stat3/S100A7 signaling Luteolin, epigallocatechin, and quercetin downregulate insulin receptors' expression via different inhibitory mechanisms [63].

Curcumin, Apigenin, kaempferol, silibinin, and genistein have shown a significant anti-proliferative effect on several cancer cells. Curcumin is an isoflavonoid isolated from turmeric predominantly found in the south and southeast of Asia and has exhibited a broad spectrum of special biological functions such as neuroprotective effect, antioxidants, and anticancer. [64] found out that curcumin, in a dose-dependent manner, is effective in the treatment of pulmonary cancer by inhibiting the signaling pathways, including VEGF, EGFR, and ERK2. Furthermore, several literature reviews of genistein have claimed that genistein consumption reduces the risk of cancer. Recent studies have reported that genistein is a potent inhibitor of protein tyrosine kinases that are majorly associated with EGFR in an ATP competitive manner [65]. The anticancer effect of myricetin, kaempferol, and quercetin by inhibiting receptor tyrosine kinases in medulloblastoma cells had been elucidated [66]. Kaempferol, silibinin, and Apigenin show promising pharmacological properties and inhibit EGFR/VEGFR/PDGFR signaling-mediated pathways [67].

Phenolic acids

Phenolic acids are usually produced by plants as secondary metabolites and are helpful in the treatment of cancer through apoptosis, alteration of proliferation, and critical pathways in cancerous cells [68]. Phenolic acids in plants work as epigenetic regulators and are used in support of conventional anticancer therapy. Phenolic acids can exist freely or bond with other molecules like esters and ethers (Fig. 5). The major anticancer components in the phenolic acid structure are the aromatic ring, unsaturated, substituted chains, and the number and position of the free hydroxyl groups [69,70,71]. They are potent in affecting cancerous cells due to their antioxidant activity and ability to inhibit cell proliferation by preventing essential protein synthesis such as receptor tyrosine kinases, thereby inducing apoptosis and stopping cellular migration and metastasis [70, 72, 73] demonstrated the potency of some phenolic compounds in the inhibition of receptor tyrosine kinases of cancerous lung cells.

Fig. 5
figure 5

Chemical structure of selected phenolic acids

Full size image

Phenolic acids alter the initiation and progression of cancer by modulating genes regulating key processes such as the oncogenic transformation of normal cells, growth and development of tumors, and angiogenesis and metastasis [74]. They are found to downregulate oncogenic survival kinases such as PI3K and Akt; cell proliferation regulators such as Erk1/2, D-type cyclins, and cyclin-dependent kinases (CDKs); transcription factors including the STATs, histone deacetylase, and growth factors VEGF, FGFR1. They also regulate tumor suppressor proteins: tumor suppressor proteins p53, PTEN, p21, and p27. Furthermore, they control reactive oxygen species (ROS) and alter cell proliferation and apoptosis [74].

Caffeic acid

Caffeic acid (CA) has been found to target receptor tyrosine kinases (RTK) in cancer treatment. The epidermal growth factor receptor (EGFR), an example of RTK, is a cell-surface receptor for epidermal growth factor. Caffeic acid suppresses the phosphorylation of EGFR in breast cancer cells [75]. The gene elevation of EGFR is associated with poor prognosis in OSCC [75, 76]. Cyclooxygenases (COX-1 and COX-2) are enzymes involved in forming prostanoids; their mRNA and protein level are regulated in OSCC and high-risk premalignant oral lesions [77]. Treatment with caffeic acids inhibits the proliferation of COX-2 in human oral squamous carcinoma cells. This treatment inhibits EGFR and COX-2, which prevents the development of oral cancers [78].

Vascular endothelial growth factor (VEGF) is also a class of RTK that promotes choroidal neovascularization (CNV) that leads to a severe loss of sight. CA inhibits the production of VEGF in retinal pigment epithelial cells (RPE cells) under hypoxic conditions. Sung et al. [79] carried out in vitro experiment by exposing human RPE cells to hypoxia with or without caffeic treatment; CA was found to suppress the hypoxia-induced production of VEGF in the RPE cells through the inhibition of reactive oxygen species (ROS) production and phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor-1α (HIF-1α) expression. This shows the promising effects of CA in the treatment of CNV.

CA is found to target platelet-derived growth factor receptor (PDGFR) in coronary artery cancer through its underlying mechanism on human coronary smooth muscle cells (SMCs). CA inhibited proliferation and migration of PDGF and induced apoptosis [80]; it alters the activation of AKT1, MEK1, and ERK1/2 signaling molecules at 10–60 min after CA treatment. CA triggered the activation of cytochrome C from mitochondria to cytosol, upregulated the proapoptotic gene Bax, and downregulated the antiapoptotic gene Bcl-2. The mitochondrion-dependent apoptotic signaling pathway is precipitated by CA, which created anti-proliferation, antimigration, and proapoptotic effects on human SMCs after PDGF stimulation [80].

CA suppresses the growth of breast cancer by targeting insulin receptors in the estrogen. Estrogen receptor (ER) is sensitive to the caffeic acid; it induced cell death in MCF-7 with reduced prosurvival Bcl-xL levels but increased active caspase-7 and cleaved PARP, leading to apoptosis [81]. CA reduced the insulin-like growth factor-I receptor (IGF-IR) and pAkt levels in both ER(+) and ER(−) cells. This effect disrupts the progression of the cell cycle and enhanced cell death.

Gallic acid (GA) shows anti-tumorigenic effects in TKI-resistant non-small cell lung cancer (NSCLC); lung cancer patients have benefited from GA as it demonstrated the tumor-suppressive effect for TKI-resistant cancer compared to the TKI-sensitive one. GA blocks the proliferation of epidermal growth factor (EGF), which induces downstream signaling pathways leading to tumor growth [82]. In the experiment of Ai et al. [83], lung cancer cells were cloned and labeled; H1650 was inhibited by GA through loss of phosphatase and tensin homolog (PTEN). Also, mutation of K-ras caused by GA suppressed the growth of the H358 cancer clone.

Gallic acid

GA is found promising for the prevention and therapy of ovarian cancer by targeting the VEGF. Based on concentration, GA inhibits the activation of VGEF and suppressed in vitro angiogenesis. GA downregulated AKT phosphorylations and HIF-1α expression, and the luciferase assay results suggest that the PTEN/AKT/HIF-1α inhibition is responsible for VEGF suppression by GA [84].

GA inhibits ligand binding and the subsequent tyrosine phosphorylation of the platelet-derived growth factor β receptor (βPDGFR), which plays a critical role in the pathogenesis of atherosclerosis. PDGF is involved in all phases of atherogenesis and artery cancer. GA inhibits the association of the βPDGFR with specific signaling molecules, including RasGAP, PLCγ, PI3K, and SHP-2, in response to PDGF-BB [85].

Previous studies suggested that the anti-proliferative effect of GA may probably be due to its potential to control oxidative stress associated with cancer cells [86]. Targeting the insulin receptor, GA produces significant levels of H2O2 and O2 in human promyelocytic leukemia HL60 and its resistant sublines HL60/VINC and HL60/MX2 cells; leading to apoptosis of cancer cells [87, 88].

An experiment on non-small cell lung cancer of mutated EGF receptor harbored in parental HCC827 cells. Treatment with chlorogenic acid (CGA) revealed that EGF is targeted in treating non-small cell lung cancer by inhibiting the clone HCC827C2 growth of the cancerous cell at a concentration of 20 µM, thereby prevents the further proliferation of the cancer cell [73].

Vascular endothelial growth factor (VEGF) activates a series of signaling pathways by binding to its receptor (VEGFR2) for proliferation effects in endothelial cells [89, 90]. This binding serves as a promising target to suppress tumor growth. The CGA scavenges the ROS, which weakens the VEGFR2-mediated signaling and phosphorylation of VEGFR2, extracellular signal-regulated kinase 1/2, and serine-threonine kinase [91].

The in vitro studies in liver cancer show that PDGF could induce NOX subunits (p47phox and gp91phox) expression, ROS production, p38 and ERK1/2 phosphorylation, the activation of HSCs, and the manifestation of profibrotic genes. CGA is found promising in the treatment of liver cancer through the inhibition of signaling pathways of PDGF. It suppresses the PDGF-induced profibrotic action by inhibiting the NOX/ROS/MAPK pathway [92].

Glucose metabolic disorders are sometimes associated with the occurrence and progression of cancer. Inhibiting the insulin receptor, CGA suppressed the activities of α-amylase and α-glucosidase and reduced the postprandial blood glucose concentration. CGA suppresses postprandial hyperglycemia by inhibiting α-glucosidase, and its action is similar to that of acarbose, miglitol, and voglibose [93].

Ferulic acid

Ferulic acid (FA) has been reported to be of importance in cancer therapy by targeting the RTK. In vitro examination in human breast cancer cells inhibit epidermal growth factor receptor (EGFR) through downregulation of Tyr 1068 autophosphorylation; molecular docking analysis revealed that FA form hydrogen bond interaction with Lys 745 and Met 793 and thereby exhibit stronger hydrophobic interactions with multiple amino acid residues at the EFGR kinase domain [94]. This result gives a good effect of FA in treating breast cancer through the alteration of EFGR proliferation.

Anticancer activity of ferulic acid is observed in the docking of the molecules of tyrosine kinase and VEGF-2 proteins in silico, which inhibits VEGF expression on the CAM model. This related to cancer cell inhibition, which is presented by inhibition of neovascularization and endothelial cell growth in blood vessels, showing that FA is a promising anticancer therapeutic agent at an early stage [95].

PDGF is a promising target in the destruction of cancer cells by FA through the up-regulation of hypoxic-induced factor (HIF) 1αmRNA and protein, which serves as the inhibitor of PDGF in humans umbilical vein endothelial cells (HUVECs) [96].

FA prevents the growth of cancerous cells through the target of the insulin receptor. Atomic force microscopy shows that FA inhibits insulin amyloid fibril. FA suppresses the characteristic conformational transition from a-helix to b-sheet, leading that FA protects the native structure of insulin and prevents the conformational change required for its amyloid fibril formation in vitro [97].

Tannic acid

Tannic acid (TA) has been reported to have anticancer activity through apoptosis. Reactive oxygen species destroy cellular structures through the reaction with biological molecules and thereby induce cancer; the scavenging activity of tannic acid prevents the ROS from prolonging tumor cells [98]. Tannic acid inhibits EGF by competing with the ATP; it was docked into the ATP-binding pockets of the EGF receptor and led to cancerous cell death [99]. The experiment made by Darvin et al. [99] revealed that the EGFR-stimulated growth of breast cancer cells was inhibited in the presence of tannic acid.

VEGF plays an essential role in angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. It also promotes proliferation, survival, migration, and differentiation of endothelial cells [100]. VEGF as a target in the destruction of cancerous cells has been promising as it increases the cell membrane expression of CXCR4, which binds to stromal-cell-derived factor-1 (SDF-1), leading to the proliferation of cancer. In human breast cancer, TA alters the proliferation of VEGF, thereby decreases the expression of CXCR4 and interrupts its binding to SDF-1 [101].

Platelet-derived growth factors play a significant role in cancer. It has been an important target in cancer therapy; TA is shown to inhibit the conventional isomers of PDGF isoforms α, βI, and βII in mouse epidermal cell lines by binding to the regulatory domain of PDGF [102, 103]. TA targets insulin receptors in cancer cells by inhibiting insulin-induced glucose transport. TA is also found to inhibit the expression of essential genes for adipogenesis [104]. Studies revealed that tannic acid inhibits insulin-stimulated autophosphorylation of the insulin receptor in streptozotocin-induced diabetic rat on a concentration basis [105].

Alkaloids

Alkaloids are one of the largest groups of natural compounds classified based on their nitrogen contain atoms at different molecule positions (Fig. 6). Alkaloids constitute structurally diverse and unrelated biomolecules. Many of the well-known alkaloids, including quinine, nicotine, morphine, and apomorphine, possess significant therapeutic potential such as antimicrobial, anticancer, antioxidant, and antispasmodic [106, 107].

Fig. 6
figure 6

Chemical structures of selected Alkaloids

Full size image

Opioids have been effectively used in treating pain in cancer patients, and their effect on vascular endothelium has been studied extensively. The pharmacological function of opioids has to be characterized majorly in the central nervous with little focus on their non-neuronal systems [108]. Opioids function by activating specific µ opioid receptors (MORs), G-protein coupled receptors associated with several cellular functions, including cell differentiation, proliferation, and survival. Opioids such as morphine have demonstrated clinical applications in cancer therapy [109]. Zhao et al. [110] discovered that long-term use of morphine therapy phosphorylates EGFR more rapidly at tyrosine 845 in c-Src-dependentSrc-dependent internalization. Administration of morphine significantly reduced the growth of tumor cells in MCF-7 breast cancer cells via inhibition of the VEGFR signaling pathway [108]. Further studies have shown that exposure of human oral cancer HSC-3 cells to morphine downregulates VEGFR expression, thereby disrupting cell proliferation. In hypoxic conditions, morphine impairs angiogenesis by inhibiting the primary stimulator of angiogenesis, VEGFR [111, 112]. However, Lu et al. [109] suggested that morphine promotes carcinogenesis by stimulating the EGFR signaling pathway. Therefore, several in vivo studies are required to establish the anticancer effect of morphine. Other alkaloids such as quinine and nicotine inhibit signaling pathways. However, their cytotoxic effect has primarily been reported in atherosclerosis, with little focus on their anticancer activity. Nicotine has been shown to promote cell proliferation in human glioma cells through activation of EGFR [113, 114].

Stilbenes

Stilbenes are a group of polyphenols and have received significant interest due to biological functions, chemical structures, and pharmacological activities. The characterization, clinical applications, and molecular mechanisms of resveratrol and its structural analog have been reported. Stilbenes undergo different secondary metabolites modifications to produce its structure derivatives, such as glycosylation, methoxylation, and oligomerization. Stilbenes are novel compounds for drug development and have demonstrated antioxidant, antitumor, antimalarial, and anti-inflammatory [115,116,117].

Resveratrol (3, 5, 4′-trihydroxystilbene) (Fig. 7) is a natural phytoalexin present in plants, and dietary sources possess several biological functions, including anti-proliferative, anti-inflammatory, and antioxidant. Consumption of resveratrol has been associated with a reduced risk of cancer and heart diseases [118]. Literature data demonstrated that administration of resveratrol at high concentration suppresses insulin in an animal model. Resveratrol inhibits angiogenesis induced by VEGFR via blocking Src tyrosine kinase, which phosphorylates vascular endothelial cadherin [119, 120]. Furthermore, resveratrol isolated from grapefruit has been shown to inhibit the downstream PDGF-R activation and EGFR signaling pathway selectively. A previous study indicated that treating human HaCaT and A431 cells with resveratrol and its methylthio-derivatives reduces overexpression of EGFR in tumor cells [121]. Zhang et al. [122] investigated the anticancer effect of resveratrol on living MCF-7cells. The result proposed that resveratrol inhibits EGFR dependent ERK activation in a dose-dependent manner. However, the molecular mechanism underlying resveratrol action on cell proliferation is not well understood [123].

Fig. 7
figure 7

Chemical structure of Resveratrol

Full size image

Lignans

Lignans are a class of naturally occurring secondary plant metabolites produced from the dimerization of two phenylpropanoid units (Fig. 8). Lignans are present majorly in their form, although their glycosides derivatives can also be present in minor conditions. They play a crucial role in plant defense mechanisms against diverse biological pathogens due to their biological properties. The anti-proliferative and cytotoxic effect of lignans has been the most studied among their biological functions. Silymarin, silydianin, and silychristin are flavonolignans with hepatoprotective activity [124,125,126].

Fig. 8
figure 8

Chemical structure of Honokiol

Full size image

Honokiol is a bioactive natural compound isolated from the bark of Magnolia. Previous studies have identified the therapeutic activity of honokiol, including anti-angiogenesis, an antioxidant, anti-inflammatory, anti-proliferative, and broad spectrum of antimicrobial [127]. Liposomal honokiol has been shown to inhibit tumor cell progression by downregulation of VEGFR-3 and induced apoptosis in cancer cell lines. Furthermore, the study suggested that honokiol effectively treats lung cancer through direct inhibition of angiogenesis and lymphangiogenesis via downregulation of vascular growth factors, VEGFR-2 and VEGFR-3 [128]. Honokiol demonstrated inhibitory potential against EGFR signaling cascade in head and neck squamous cell carcinoma (HNSCC) by arresting cellular proteins of the G0-G1 phase in a dose-dependent manner [129, 130]. Park et al. [130] reported that honokiol block the proliferation of MDA-MB-231 cells through downstream inhibition of c-Src/ EGFR-induced signaling pathway.

Conclusions

Natural compounds have substantially been characterized as a secondary metabolite of plants, demonstrating biological and pharmacological properties in preventing the progression of tumors and adjunct cancer therapy. Given the fundamental role of RTKs in signal transduction pathways that leads to tumorigenesis, several RTK inhibitors have been developed to effectively treat cancer. Furthermore, the use of natural products as ATP-competitive inhibitors of RTKs can reduce side effects and lower toxicity associated with small molecules such as imatinib, gefitinib, and erlotinib. Translational studies have always proven to be a barrier in scientific research, as only few are embarked on. It is no news that the pharmacological potential of natural products in the treatment of several metabolic diseases have been properly documented. As such, future studies should translate the natural products studied in this review into in vivo studies and if possible, clinical trials. Howbeit, synergistic relationship between several phytochemicals could prove efficient in managing cancer. Thus, studies on the synergistic mechanism of action of several natural compounds in the management of cancer could pave a novel path in ameliorating the jab thrown by the oncogenic ring in cancer.

Availability of data and material

Not applicable.

Abbreviations

RTK:

Receptor tyrosine kinases

EGFR:

Endothelial growth factor receptor

PDGF:

Platelet-derived growth factor receptor

VEGFR:

Vascular endothelial growth factor receptor

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

COX:

Cyclooxygenases

ERK:

Extracellular signal-regulated kinase

PI3K:

Phosphoinositide 3-kinase

PKB:

Protein kinase B (PKB) also known as Akt

JNK:

C-Jun N-terminal kinases

IGFR:

Insulin growth factor receptor

PTB:

Phosphotyrosine binding

SH2:

Src homology

TKD:

Tyrosine kinase domain

HER:

Human epidermal growth factor receptor

PTEN:

Phosphatase and tensin homolog

MAPK:

Mitogen-activated protein kinases

NSCLC:

Non-small cell lung cancer

H2O2:

Hydrogen peroxide

SDF-1:

Stromal-cell-derived factor-1

JAK:

Janus kinases

STAT:

Signal transducer and activator of transcription proteins

PLCγ:

Phospholipase-γ

CryoEM:

Cryo-electron microscope

IRS:

Insulin receptor substrate

CDKs:

Cyclin kinases

FGFR:

Fibroblast growth factor receptor

HIF-1α:

Hypoxia-inducible factor-1α

SMCs:

Smooth muscle cells

References

  1. Dervisis N, Klahn S (2016) Therapeutic innovations: tyrosine kinase inhibitors in cancer. Vet Sci 3:4–8

    Article  Google Scholar 

  2. Mitchison TJ (2012) The proliferation rate paradox in antimitotic chemotherapy. Mol Biol Cell 23:1e6. doi:https://doi.org/10.1091/mbc.E10-04-0335.

  3. Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9:28e39. doi:https://doi.org/10.1038/nrc2559.

  4. Jeanne PA, Gray N, Settleman J (2009). Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov 8:709e23.

  5. Oh DY, Bang YJ (2020) HER2-targeted therapies - a role beyond breast cancer. Nat Rev Clin Oncol 17(1):33–48. https://doi.org/10.1038/s41571-019-0268-3

    CAS  Article  PubMed  Google Scholar 

  6. Valiathan RR, M. Marco B, Leitinger CG, Kleer R, Fridman, Discoidin (2012) Domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev. 31:295e321.

  7. Shanmugam MK, Rane G, Kanchi MM, Arfuso FA et al (2015) The multifaceted role of curcumin in cancer prevention and treatment. Molecules 20:2728e69.

  8. Vella V, Giuliano M, Nicolosi ML et al (2021) DDR1 affects metabolic reprogramming in breast cancer cells by cross-talking to the insulin/IGF system. Biomolecules 11(7):926

    Article  Google Scholar 

  9. Kim HG, Hwang SY, Aaronson SA, Mandinova A, Lee SW (2011) DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation. J Biol Chem 286:17672e81.

  10. Kumar R, Pereira RS, Zanetti C et al (2020) Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia. Leukemia 34(8):2087–2101. https://doi.org/10.1038/s41375-020-0866-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Hemalswarya S, Doble M (2006) Potential synergism of natural products in the treatment of cancer, Phyther Res 20:239e49.

  12. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134. https://doi.org/10.1016/j.cell.2010.06.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Priyadarsini KI (2014) The chemistry of curcumin: from extraction to therapeutic agent. Molecules 19:20091e112.

  14. Jin N, Bi A, Lan X et al (2019) Identification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer. Nat Commun 10(1):2701

    Article  Google Scholar 

  15. Choura M, Rebaï A (2011) Receptor tyrosine kinases : from biology to pathology. J Recept Signal Transduct Res 31(6):387–394. https://doi.org/10.3109/10799893.2011.625425

    CAS  Article  PubMed  Google Scholar 

  16. Clayton AHA et al (2005) Ligand-induced dimer-tetramer transition during the activation of the cell surface epidermal growth factor receptor: a multidimensional microscopy analysis. J Biol Chem 280(34):30392–30399. https://doi.org/10.1074/jbc.M504770200

    CAS  Article  PubMed  Google Scholar 

  17. Lemmon MA, Joseph S (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134

    CAS  Article  Google Scholar 

  18. Ren S et al (2008) The conservation pattern of short linear motifs is highly correlated with the function of interacting protein domains. BMC Genomics 9:1–13

    Article  Google Scholar 

  19. Metibemu D,Samuel, et al (2019) Exploring receptor tyrosine kinases-inhibitors in cancer treatments. Egypt J Med Hum Genet 20(1):1–16

    Article  Google Scholar 

  20. Koch S, Xiujuan L, Laura G, and Lena C (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437(2):169–83. doi: https://doi.org/10.1042/BJ20110301

  21. Holmes K, Owain LR, Thomas AM, Michael JC (2012) Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 19(10):2003–2012. https://doi.org/10.1016/j.cellsig.2007.05.013

    CAS  Article  Google Scholar 

  22. Wiszniak S, Schwarz Q (2021) Exploring the intracrine functions of VEGF-A. Biomolecules 11(1):128

    CAS  Article  Google Scholar 

  23. Karaman S, and Veli-matti L (2018) Vascular endothelial growth factor signaling in development and disease. Development. 145(14):dev151019. doi: https://doi.org/10.1242/dev.151019.

  24. Claesson-Welsh L (2008) VEGF-B taken to our hearts: specific effect of VEGF-B in myocardial ischemia. Arterioscler Thromb Vasc Biol 28(9):1575–1576

    CAS  Article  Google Scholar 

  25. Li W et al. (2020) Clinical use of vascular endothelial growth factor receptor inhibitors for the treatment of renal cell carcinoma. Eur J Med Chem 15(200):112482. doi: https://doi.org/10.1016/j.ejmech.2020.112482.

  26. Stacker SA, Achen MG (2018) Emerging roles for VEGF-D in human disease. Biomolecules 8(1):1. https://doi.org/10.3390/biom8010001

    CAS  Article  PubMed Central  Google Scholar 

  27. Mendelsohn J, Jose B (2006) Epidermal growth factor receptor targeting in cancer. Semin Oncol 33(4):369–385. https://doi.org/10.1053/j.seminoncol.2006.04.003

    CAS  Article  PubMed  Google Scholar 

  28. Liu X, Ping W, Caiyan Z, Zhongliang M (2017) Epidermal growth factor receptor (EGFR ): a rising star in the era of precision medicine of lung cancer. Oncotarget 8(30):50209–50220

    Article  Google Scholar 

  29. Kovacs E, Julie AZ, Yongjian H, and Tiago B (2015) A Structural Perspective on the Regulation of the Epidermal Growth Factor Receptor. Annu Rev Biochem. 84:13.1–13.26 doi:https://doi.org/10.1146/annurev-biochem-060614-034402.

  30. Liang W et al (2014) Network meta-analysis of erlotinib, gefitinib, afatinib and icotinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. PLoS ONE 9(2):e85245. https://doi.org/10.1371/journal.pone.0085245

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Wang Y, Yang N, Zhang Y et al (2020) Effective treatment of lung adenocarcinoma harboring EGFR-activating mutation, T790M, and cis-C797S triple mutations by brigatinib and cetuximab combination therapy. J Thorac Oncol 15(8):1369–1375

    CAS  Article  Google Scholar 

  32. Jorissen, Robert N et al (2018) Epidermal growth factor receptor: mechanisms of activation and signalling 284(1):31–53. doi:https://doi.org/10.1016/s0014-4827(02)00098-8.

  33. Du Z, Christine ML (2018) Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer 17(1):58. https://doi.org/10.1186/s12943-018-0782-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Kazlauskas A (2017) PDGFs and their receptors. Gene 614:1–7. https://doi.org/10.1016/j.gene.2017.03.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Kramer F, Dernedde J, Mezheyeuski A, Tauber R, Micke P, Kappert K (2020) Platelet-derived growth factor receptor β activation and regulation in murine myelofibrosis. Haematologica 105(8):2083–2094

    CAS  Article  Google Scholar 

  36. Shen S, Wang F, Fernandez A, Hu W (2020) Role of platelet-derived growth factor in type II diabetes mellitus and its complications. Diab Vasc Dis Res 17(7):1479164120942119

    PubMed  PubMed Central  Google Scholar 

  37. Andrae J, Radiosa G, Christer B (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22(10):1276–1312

    CAS  Article  Google Scholar 

  38. Haeusler RA, McGraw TE, Accili D (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19(1):31–44

    CAS  Article  Google Scholar 

  39. De Meyts P (2004) Insulin and Its receptor: structure. Funct Evol Bioessays 7:1351–1362

    Article  Google Scholar 

  40. Scapin G, Dandey VP, Zhang Z et al (2018) Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis. Nature 556(7699):122–125. https://doi.org/10.1038/nature26153

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Belfiore A et al (2014) Insulin receptor isoforms and insulin receptor / insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30:586–623

    Article  Google Scholar 

  42. A Kasuga M (2019). Structure and function of the insulin receptor-a personal perspective. Proc Jpn Acad Ser B Phys Biol Sci 95(10):581–589. https://doi.org/10.2183/pjab.95.039

  43. Machairiotis N, Sofia V, Paraskevi K (2019) Structure and function of the insulin receptor-a personal perspective. Proc Jpn Acad Ser B Phys Biol Sci 95(10):581–589. https://doi.org/10.1016/j.ejogrb.2019.11.019

    CAS  Article  Google Scholar 

  44. Lichota A, Krzysztof G (2018) Anticancer activity of natural compounds from plant and marine environment. Int J Mol Sci 19:3533. https://doi.org/10.3390/ijms19113533

    CAS  Article  PubMed Central  Google Scholar 

  45. Fidyt K, Fiedorowicz A, Strządała L, Szumny A (2016) β-caryophyllene and β-caryophyllene oxide-natural compounds of anticancer and analgesic properties. Cancer Med 5(10):3007–3017. https://doi.org/10.1002/cam4.816

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Ong CP, Wai LL, Yin QT, Wei HY (2020) Honokiol: a review of its anticancer potential and mechanisms. Cancers 1:1–51

    Google Scholar 

  47. Baier A (2020) Compounds from natural sources as protein kinase inhibitors. Biomolecules 10:1546. https://doi.org/10.3390/biom10111546

    CAS  Article  PubMed Central  Google Scholar 

  48. Teillet F, Ahcene B, Jean B, Xavier R (2007) Flavonoids as RTK inhibitors and potential anticancer agents. Med Res Rev 28(5):715–745. https://doi.org/10.1002/med.20122

    CAS  Article  Google Scholar 

  49. Rauf A, Imran M, Khan IA, Ur-Rehman M, Gilani SA, Mehmood Z, Mubarak MS (2018) Anticancer potential of quercetin: a comprehensive review. Phytother Res 32(11):2109–2130. https://doi.org/10.1002/ptr.6155

    CAS  Article  PubMed  Google Scholar 

  50. Zheng S-Y et al (2012) Anticancer effect and apoptosis induction by quercetin in the human lung cancer cell line A-549. Mol Med Rep 5(3):822–826. https://doi.org/10.3892/mmr.2011.726

    CAS  Article  PubMed  Google Scholar 

  51. Choi EJ, Su MB, Woong SA (2008) Antiproliferative effects of quercetin through cell cycle arrest and apoptosis in human breast cancer MDA-MB-453 cells. Arch Pharm Res 31(10):1281–1285

    CAS  Article  Google Scholar 

  52. Zhao D et al (2014) Inhibitory effects of quercetin on angiogenesis in Larval Zebra Fish and human umbilical vein endothelial cells. Eur J Pharmacol 723:360–367. https://doi.org/10.1016/j.ejphar.2013.10.069

    CAS  Article  PubMed  Google Scholar 

  53. Haghi A, Azimi H, Rahimi R (2017) A comprehensive review on pharmacotherapeutics of three phytochemicals, curcumin, quercetin, and allicin, in the treatment of gastric cancer. J Gastrointest Cancer 48(4):314–320

    CAS  Article  Google Scholar 

  54. Pu Y et al (2018) Luteolin exerts an anticancer effect on gastric cancer cells through multiple signaling pathways and regulating MiRNAs. J Cancer 9(20):3669–3675. https://doi.org/10.7150/jca.27183

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Sun S, Fanger G, Ping L, Qilong M (2018) Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway. Gene 20(664):50–57. https://doi.org/10.1016/j.gene.2018.04.045

    CAS  Article  Google Scholar 

  56. Donnini S et al (2006) Divergent effects of quercetin conjugates on angiogenesis. Br J Nutr 95(5):1016–1023. https://doi.org/10.1079/bjn20061753

    CAS  Article  PubMed  Google Scholar 

  57. Arunakaran J (2014) Function chemopreventive agent against prostate cancer in an in vivo model by inhibiting the EGFR signaling pathway. Food Funct 5:2632–2645. https://doi.org/10.1039/C4FO00255E

    CAS  Article  PubMed  Google Scholar 

  58. Lee J, Song H, Jeong Y, Jae HK (2015) Quercetin 3-O-glucoside suppresses epidermal growth factor: induced migration by inhibiting EGFR signaling in pancreatic cancer cells. Tumour Biol 36(12):9385–9393. https://doi.org/10.1007/s13277-015-3682-x

    CAS  Article  PubMed  Google Scholar 

  59. Bhattacharyya N, Pechhold K, Shahjee H, Zappala G, Elbi C, Raaka B, Wiench M, Hong J, Rechler MM (2006) Nonsecreted insulin-like growth factor binding protein-3 (IGFBP-3) can induce apoptosis in human prostate cancer cells by IGF-independent mechanisms without being concentrated in the nucleus. J Biol Chem 281(34):24588–24601. https://doi.org/10.1074/jbc.M509463200

    CAS  Article  PubMed  Google Scholar 

  60. Ishizawa K et al (2009) Quercetin Glucuronide Inhibits Cell Migration and Proliferation by Platelet-Derived Growth factor in vascular smooth muscle cells. J Pharmacol Sci 264:257–64.

  61. Huang C-Y et al (2013) Quercetin induces growth arrest through activation of FOXO1 transcription factor in EGFR-overexpressing oral cancer cells. J Nutr Biochem 24(9):1596–1603. https://doi.org/10.1016/j.jnutbio.2013.01.010

    CAS  Article  PubMed  Google Scholar 

  62. Fan JJ, Hsu WH, Lee KH et al (2019) Dietary flavonoids luteolin and Quercetin inhibit migration and invasion of squamous carcinoma through reduction of Src/Stat3/S100A7 signaling. Antioxidants (Basel) 8(11):557

    CAS  Article  Google Scholar 

  63. Shao L et al (2013) Opposite effects of quercetin, luteolin, and epigallocatechin gallate on insulin sensitivity under normal and inflammatory conditions in mice. Inflammation 36(1):1–14. https://doi.org/10.1007/s10753-012-9514

    CAS  Article  PubMed  Google Scholar 

  64. Yu-tang T et al (2011) Curcumin reduces pulmonary tumorigenesis in vascular endothelial growth factor ( VEGF )-overexpressing transgenic mice. Mol Nutr Food Res 55(7):1036–1043. https://doi.org/10.1002/mnfr.201000654

    CAS  Article  Google Scholar 

  65. Russo M et al (2016) Understanding genistein in cancer : the ‘‘ good ” and the ‘‘ bad ” effects : a review. Food Chem 196:589–600

    CAS  Article  Google Scholar 

  66. Normanno N et al (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Cancers 366:2–16

    CAS  Google Scholar 

  67. Lee J, Jae HK (2016) Kaempferol Inhibits pancreatic cancer cell growth and migration through the blockade of EGFR-related pathway in vitro. PLoS ONE 11(5):e0155264. https://doi.org/10.1371/journal.pone.0155264

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Mariam A, Alena L, Peter K, Dietrich B (2020) Therapeutic potential of plant phenolic acids in the treatment of cancer. Biomolecules 10:221. https://doi.org/10.3390/biom10020221

    CAS  Article  Google Scholar 

  69. Anantharaju PG, Gowda PC, Vimalambike MG, Madhunapantula SV (2016) An overview on the role of dietary phenolics for the treatment of cancers. Nutr J 15:99

    Article  Google Scholar 

  70. Ls R, Nja S (2016) Anticancer properties of phenolic acids in colon cancer: a review. J Nutr Food Sci 6:10–4172. https://doi.org/10.4172/2155-9600.1000468

    CAS  Article  Google Scholar 

  71. Rahman MJ, Costa DCA, Shahidi F (2018) Phenolic profiles and antioxidant activity of defatted camelina and sophia seeds. Food Chem 240:917–925. https://doi.org/10.1016/j.foodchem.2017.07.098

    CAS  Article  PubMed  Google Scholar 

  72. Srinivasulu C, Ramgopal M, Ramanjaneyulu G, Anuradha CM, Suresh KC (2018) Syringic acid (SA) a review of its occurrence, biosynthesis, pharmacological and industrial importance. Biomed Pharmacother 108:547–557. https://doi.org/10.1515/ncrs-2020-0632

    CAS  Article  PubMed  Google Scholar 

  73. Hyungmin J, Ai NH, Jong WC (2017) Anti-cancer effects of polyphenolic compounds in epidermal growth factor receptor tyrosine kinase inhibitor-resistant non-small cell lung cancer. Pharmacogn Mag 13:52. https://doi.org/10.4103/pm.pm_535_16

    CAS  Article  Google Scholar 

  74. Preethi GA, Prathima CG, Manjunatha GV, SubbaRao VM (2016) An overview on the role of dietary phenolics for the treatment of cancers. Nutr J 15:99. https://doi.org/10.1186/s12937-016-0217-2

    CAS  Article  Google Scholar 

  75. Ning X, Ren X, Xie X, Yan P, Wang D, Huang X (2020) A caffeic acid phenethyl ester analog inhibits the proliferation of nasopharyngeal carcinoma cells via targeting epidermal growth factor receptor. J Biochem Mol Toxicol 34(7):e22491

  76. Chien HT, Cheng SD, Liao CT, Wang HM, Huang SF (2019) Amplification of the EGFR and CCND1 are coordinated and play important roles in the progression of oral squamous cell carcinomas. Cancers (Basel) 11(6):760

    CAS  Article  Google Scholar 

  77. Huang GZ, Wu QQ, Zheng ZN, Shao TR, Lv XZ (2019) Identification of candidate biomarkers and analysis of prognostic values in oral squamous cell carcinoma. Front Oncol 9:1054

    Article  Google Scholar 

  78. Kuo YY, Jim WT, Su LC et al (2015) Caffeic acid phenethyl ester is a potential therapeutic agent for oral cancer. Int J Mol Sci 16(5):10748–10766

    CAS  Article  Google Scholar 

  79. Sung HP, Won-Kyo J, Won SP, Dae SL, Gi YK, Yung HC, Su KS, Won HJ, Jung SC, Young ML, Saegwang P, Whan C (2015) Caffeic acid phenethyl ester reduces the secretion of vascular endothelial growth factor through the inhibition of the ROS, PI3K and HIF-1α signaling pathways in human retinal pigment epithelial cells under hypoxic conditions. Int J Mol Med 35:1419–1426. https://doi.org/10.3892/ijmm.2015.2116

    CAS  Article  Google Scholar 

  80. Hung CH, Ho CC, Chin TT, Chan YK (2012) Caffeic acid phenethyl ester inhibits proliferation and migration, and induces apoptosis in platelet-derived growth factor-BB-stimulated human coronary smooth muscle cells. J Vasc Res 49(1):24–32. https://doi.org/10.1159/000329819

    CAS  Article  Google Scholar 

  81. Ann HR, Claire MP, Li Z, Andrea M, Maria S, Carsten R, Christian I, Jeff MP, Holly HJ (2015) Caffeine and caffeic acid inhibit growth and modify estrogen receptor and insulin-like growth factor i receptor levels in human breast cancer. Clinical cancer Resources 21(8):1877–1887. https://doi.org/10.1158/1078-0432.CCR-14-1748

    CAS  Article  Google Scholar 

  82. Chong CR, Janne PA (2013) The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 19:1389–1400. https://doi.org/10.1038/nm.3388

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. Ai NH, Tuyen NM, Hua MK, Vu TA, Jong WC, Hyun WK, Jin KR, Ki WK, Yangsik J (2016) Gallic acid inhibition of Src-Stat3 signaling overcomes acquired resistance to EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer. Oncotarget 7(34):54702–54713. https://doi.org/10.18632/oncotarget.10581

    Article  Google Scholar 

  84. Zhiping H, Allen YC, Yon R, Gary OR, Yi CC (2016) Gallic acid, a phenolic compound, exerts anti-angiogenic effects via the PTEN/AKT/HIF-1α/VEGF signaling pathway in ovarian cancer cells. Oncol Rep 35:291–297. https://doi.org/10.3892/or.2015.4354

    CAS  Article  Google Scholar 

  85. Chen Y, Zhou G, Ma B, Tong J, Wang Y (2019) Active constituent in the ethyl acetate extract fraction of Terminalia bellirica fruit exhibits antioxidation, antifibrosis, and proapoptosis capabilities in vitro. Oxid Med Cell Longev 2019:5176090. https://doi.org/10.1155/2019/5176090

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. Mileo AM, Miccadei S (2016) Polyphenols as modulator of oxidative stress in cancer disease: new therapeutic strategies. Oxid Med Cell Longev 17:6475624. https://doi.org/10.1155/2016/6475624

    CAS  Article  Google Scholar 

  87. Russell LH, Mazzio E, Badisa RB (2012) Autoxidation of gallic acid induces ROS dependent death in human prostate cancer LNCaP cells. Anticancer Res 32(5):1595–1602

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Maruszewska A, Tarasiuk J (2019) Antitumour effects of selected plant polyphenols, gallic acid and ellagic acid, on sensitive and multidrug-resistant leukaemia HL60 cells. Phytother Res 33(4):1208–1221. https://doi.org/10.1002/ptr.6317

    CAS  Article  PubMed  Google Scholar 

  89. Ghafouri S, Burkenroad A, Pantuck M et al (2021) VEGF inhibition in urothelial cancer: the past, present and future. World J Urol 39(3):741–749. https://doi.org/10.1007/s00345-020-03213-z

    CAS  Article  PubMed  Google Scholar 

  90. El Baba N, Farran M, Khalil EA, Jaafar L, Fakhoury I, El-Sibai M (2020) The role of rho GTPases in VEGF signaling in cancer cells. Anal Cell Pathol (Amst) 2020:2097214. https://doi.org/10.1155/2020/2097214

    CAS  Article  Google Scholar 

  91. Shaoling L, Jiamiao H, Xuelin Z, Peter CK (2017) Inhibition of vascular endothelial growth factor-induced angiogenesis by chlorogenic acid via targeting the vascular endothelial growth factor receptor 2-mediated signaling pathway. J Funct Foods 32:285–295

    Article  Google Scholar 

  92. Haitao S, Ameng S, Lei D, Xiaolan L, Yan W, Juhui Z, Fei D, Xiaoyan G (2016) Chlorogenic acid protects against liver fibrosis in vivo and in vitro through inhibition of oxidative stress. Clin Nutr 35(6):1366–1373. https://doi.org/10.1016/j.clnu.2016.03.002

    CAS  Article  Google Scholar 

  93. Yan Y, Zhou X, Guo K, Zhou F, Yang H (2020) Use of chlorogenic acid against diabetes mellitus and its complications. J Immunol Res 2020:9680508. https://doi.org/10.1155/2020/9680508

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Sudhagar S, Sathya S, Anuradha R, Gokulapriya G, Geetharani Y, Lakshmi BS (2018) Inhibition of epidermal growth factor receptor by ferulic acid and 4-vinylguaiacol in human breast cancer cells. Biotechnology Lett 40(2):257–262. https://doi.org/10.1007/s10529-017-2475-2

    CAS  Article  Google Scholar 

  95. Senawong T, Khaopha S, Misuna S, Komaikul J, Senawong G, Wongphakham P (2014) Phenolic acid composition and anticancer activity against human cancer cell lines of the commercially available fermentation products of Houttuynia cordata. Science Asia 40(6):420. https://doi.org/10.2306/scienceasia1513-1874.2014.40.420

    Article  Google Scholar 

  96. Chiu ML, Jen HC, Hsing W, Bao WW, Chun MP, Yen HS (2010) Ferulic acid augments angiogenesis via VEGF, PDFG and HIF-1α. Nutr Biochem 21(7):627–633. https://doi.org/10.1016/j.jnutbio.2009.04.001

    CAS  Article  Google Scholar 

  97. Jayaraman J, Ganesh S, Ettayapuram RA (2014) Inhibition of insulin amyloid fibril formation by ferulic acid, a natural compound found in many vegetables and fruits. R Soc Chem 4:62326. https://doi.org/10.1039/C4RA11291A

    Article  Google Scholar 

  98. Andrade RG, Jr, Dalvi LT, Silva JM, Lopes GK, Alonso A, Hermes LM (2005) The antioxidant effect of tannic acid on the in vitro copper-mediated formation of free radicals. Arch Biochem Biophys 437(1):1-9. doi:https://doi.org/10.1016/j.abb.2005.02.016

  99. Darvin P, Joung YH, Kang DY et al (2017) Tannic acid inhibits EGFR/STAT1/3 and enhances p38/STAT1 signalling axis in breast cancer cells. J Cell Mol Med 21(4):720–734. https://doi.org/10.1111/jcmm.13015

    CAS  Article  PubMed  Google Scholar 

  100. Stacker SA, Achen MG (2013) The VEGF signaling pathway in cancer: the road ahead. Chin J Cancer 32:297–302. https://doi.org/10.5732/cjc.012.10319

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. Kevin M, Devin T, Byron M, Kin O (2005) Tannic acid derivatives display anti-angiogenic properties in human breast cancer cells by interfering with CXCR/SDF-1 interactions. Can Res 46:5190

    Google Scholar 

  102. Szaefer H, Kaczmarek J, Rybczynska M, Baer-Dubowska W (2007) The effect of plant phenols on the expression and activity of phorbol ester-induced PKC in mouse epidermis. Toxicology 230:1–10. https://doi.org/10.1016/j.tox.2006.10.001

    CAS  Article  PubMed  Google Scholar 

  103. Andrea B, Ryszard S (2020) Compounds from natural sources as protein kinase inhibitors. Biomolecules 10:1546. https://doi.org/10.3390/biom10111546

    CAS  Article  Google Scholar 

  104. Xueqing L, Jae-kyung K, Yunsheng L, Li J, Fang L, Xiaozhuo C (2005) Tannic acid stimulates glucose transport and inhibits adipocyte differentiation in 3T3-L1 cells. J Nutr 135:165–171. https://doi.org/10.1093/jn/135.2.165

    Article  Google Scholar 

  105. Esmaie EM, Abo-Youssef AM, Tohamy MA (2019) Antidiabetic and antioxidant effects of tannic acid and melatonin on streptozotocin induced diabetes in rats. Pak J Pharm Sci 32(4):1453–1459

    CAS  PubMed  Google Scholar 

  106. Chaves SK, Feitosa CM, da S Araújo L (2016) Alkaloids pharmacological activities - prospects for the development of phytopharmaceuticals for neurodegenerative diseases. Curr Pharm Biotechnol. 17(7):629-35. doi: https://doi.org/10.2174/138920101707160503201541.

  107. Arpita R (2017) A review on the alkaloids an important therapeutic compound from plants. Int J Plant Biotechnol 3(2):1–9

    Google Scholar 

  108. Kiyatkin EA (2019) Respiratory depression and brain hypoxia induced by opioid drugs: morphine, oxycodone, heroin, and fentanyl. Neuropharmacology 151:219–226. https://doi.org/10.1016/j.neuropharm

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. Lu H et al (2020) Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer. J Cell Physiol 236(6):4445–4454. https://doi.org/10.1002/jcp.30161

    CAS  Article  PubMed  Google Scholar 

  110. Zhao H, Gencheng W, Xiaoding C (2013) EGFR dependent subcellular communication was responsible for morphine mediated AC superactivation. Cell Signal 25(2):417–428. https://doi.org/10.1016/j.cellsig.2012.10.016

    CAS  Article  PubMed  Google Scholar 

  111. Amaram-Davila J, Davis M, Reddy A (2020) Opioids and cancer mortality. Curr Treat Options Oncol 21(3):22. https://doi.org/10.1007/s11864-020-0713-7

    Article  PubMed  Google Scholar 

  112. Nishiwada T, Yoshitaka K, Keiko U, Masahiko K (2019) Morphine inhibits cell viability and growth via suppression of vascular endothelial growth factor in human oral cancer HSC-3 cells. J Anesth 33(3):408–415. https://doi.org/10.1007/s00540-019-02645-1

    Article  PubMed  Google Scholar 

  113. Kanda Y, Yasuhiro W (2007) Nicotine-induced vascular endothelial growth factor release via the EGFR-ERK pathway in rat vascular smooth muscle cells. Life Sci 80:1409–1414. https://doi.org/10.1016/j.lfs.2006.12.033

    CAS  Article  PubMed  Google Scholar 

  114. Khalil AA, Mark JJ, Theodore DC (2013) Nicotine enhances proliferation, migration, and radioresistance of human malignant glioma cells through EGFR activation. Brain Tumor Pathol 30(2):73–83. https://doi.org/10.1007/s10014-012-0101-5

    CAS  Article  PubMed  Google Scholar 

  115. Chong J, Anne P, Philippe H (2009) Plant science metabolism and roles of stilbenes in plants. Plant Sci 177:143–155

    CAS  Article  Google Scholar 

  116. Toni E et al (2018) A review of dietary stilbenes: sources and bioavailability. Phytochem Rev 9:1007–1029

    Google Scholar 

  117. Shen T, Xiao-ning W, Hong-xiang L (2009) Natural stilbenes: an overview. Nat Prod Rep 26:916–935. https://doi.org/10.1039/b905960a

    CAS  Article  PubMed  Google Scholar 

  118. Hu WH, Dai DK, Zheng BZ et al (2020) Piceatannol, a natural analog of resveratrol, exerts anti-angiogenic efficiencies by blockage of vascular endothelial growth factor binding to its receptor. Molecules 25(17):3769. https://doi.org/10.3390/molecules25173769

    CAS  Article  PubMed Central  Google Scholar 

  119. Szkudelski T (2008) The insulin-suppressive effect of resveratrol - an in vitro and in vivo phenomenon. Life Sci 82(7–8):430–435. https://doi.org/10.1016/j.lfs.2007.12.008

    CAS  Article  PubMed  Google Scholar 

  120. Cichocki M, Hanna S, Wanda B (2014) The effect of resveratrol and its methylthio-derivatives on EGFR and Stat3 activation in human HaCaT and A431 cells. Mol Cell Biochem 396(1–2):221–228. https://doi.org/10.1007/s11010-014-2157-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. Zhang Lu et al (2014) Biosensors and bioelectronics in-situ detection of resveratrol inhibition effect on epidermal growth factor receptor of living MCF-7 cells by atomic force microscopy. Biosens Bioelectron 56:271–277. https://doi.org/10.1016/j.bios.2014.01.024

    CAS  Article  PubMed  Google Scholar 

  122. Bhaskara VK, Mittal B, Mysorekar VV, Amaresh N, Simal-Gandara J (2020) Resveratrol, cancer and cancer stem cells: a review on past to future. Curr Res Food Sci 3:284–295. https://doi.org/10.1016/j.crfs.2020.10.004

    Article  PubMed  PubMed Central  Google Scholar 

  123. Marcotullio MC (2018) An ethnopharmacological, phytochemical and pharmacological review on lignans from Mexican Bursera Spp. Molecules 23:1976. https://doi.org/10.3390/molecules23081976

    CAS  Article  PubMed Central  Google Scholar 

  124. Saleem M, Ja K, Shaiq A, Yong S (2005) An update on bioactive plant lignans. Nat Prod Rep 22(6):696–716. https://doi.org/10.1039/b514045p

    CAS  Article  PubMed  Google Scholar 

  125. Sharma DK (2006) Pharmacological properties of flavonoids including flavonolignans – integration of petrocrops with drug development from plants. J Sci Ind Res 65:477–484

    CAS  Google Scholar 

  126. Arora, S et al (2012) Honokiol: a novel natural agent for cancer prevention and therapy. Curr Mol Med 562: 1244–52

  127. Wen J et al (2009) Liposomal Honokiol Inhibits VEGF-D-Induced Lymphangiogenesis and Metastasis in Xenograft Tumor Model. Int J Cancer 2718:2709–2718

    Article  Google Scholar 

  128. Leeman N, Rebecca J et al (2010) Honokiol inhibits epidermal growth factor receptor signaling and enhances the antitumor effects of epidermal growth factor receptor inhibitors honokiol inhibits epidermal growth factor receptor signaling and enhances the antitumor effects of epidermal growth factor receptor inhibitors. Clin Cancer Res 16:2571–2579. https://doi.org/10.1158/1078-0432.CCR-10-0333

    Article  Google Scholar 

  129. Singh T (2015) Honokiol inhibits the growth of head and neck squamous cell carcinoma by targeting epidermal growth factor. Receptor 6(25):21268–21282

    Google Scholar 

  130. Park E et al (2009) Down-regulation of c-Src/EGFR-mediated signaling activation is involved in the honokiol-induced cell cycle arrest and apoptosis in MDA-MB-231 human breast cancer cells. Cancer Lett 277(2):133–140. https://doi.org/10.1016/j.canlet.2008.11.029

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge our teachers for making this study a success.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Nigeria

    Toheeb A. Balogun & Damilola A. Omoboyowa

  2. Department of Microbiology, Federal University of Technology, Akure, Nigeria

    Oluwasegun M. Ige

  3. Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria

    Abdullahi O. Alausa

  4. Department of Medical Laboratory Science, University of Nigeria, Enugu, Nigeria

    Chijioke O. Onyeani

  5. Department of Biochemistry and Molecular Biology, Federal University Dutsin-Ma, Katsina, Nigeria

    Zainab A. Tiamiyu

  6. Department of Environmental Toxicology, University of Duisburg-Essen, North Rhine-Westphalia, Germany

    Oluwatosin A. Saibu

  7. Department of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria

    Olayemi T. Abdullateef

Authors
  1. Toheeb A. Balogun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oluwasegun M. Ige
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdullahi O. Alausa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chijioke O. Onyeani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zainab A. Tiamiyu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Damilola A. Omoboyowa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Oluwatosin A. Saibu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Olayemi T. Abdullateef
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TAB conceived and designed the work. TAB, OMI, and AOA collected data, wrote the original draft, reviewed and edited. COO, ZAT, OAS, and OTA assisted with data collection and editorial works. DAO supervised the project. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Toheeb A. Balogun.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Balogun, T.A., Ige, O.M., Alausa, A.O. et al. Receptor tyrosine kinases as a therapeutic target by natural compounds in cancer treatment. Futur J Pharm Sci 7, 197 (2021). https://doi.org/10.1186/s43094-021-00346-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43094-021-00346-9

Keywords

  • Receptor tyrosine kinases
  • Cancer
  • Natural products
  • Signal transduction
  • Flavonoids