Introduction

Cancer is a serious health challenge globally, with 2020 statistics showing that more than 19 million new cases and approximately 10 million deaths occurred. It is estimated that new cancer cases worldwide will increase by approximately 50% in 20 years (Mao et al. 2022). Currently, breast cancer is the most common cancer, with approximately 2.3 million new patients each year. The next most frequent types are lung, colorectal, prostate, and stomach cancers. However, lung cancer is the leading cause of cancer-related mortality, with approximately 1.8 million deaths each year, followed by colorectal, liver, stomach, and breast cancers (Sung et al. 2021). Evidence from clinical research suggests that a poor diet, obesity, and insufficient exercise habits may increase cancer risk. Many cancer cases can be treated, with current common treatment methods, including chemotherapy, hormone therapy, immunotherapy, and targeted therapy (Siegel et al. 2022; Rock et al. 2022). Therefore, identifying new therapeutic agents with specific effects on different tumor types is necessary.

MAPK pathway is a highly conserved tertiary kinase model (He and Meng 2020) that is mainly composed of MAPKKK, MAPKK, and MAPK (Park and Baek 2022). Intracellular and extracellular signals stimulate the upstream kinase MAPKKK, which responds by activating the intermediate kinase MAPKK. This then activates the downstream kinase MAPK (Lee et al. 2020). In mammals, there are more than a dozen proteins in the model of the tertiary kinase of MAPK. The four most common subprotein families include the ERK1/2, JNK, p38, and ERK5 families (Cargnello and Roux 2011). MAPK pathway signaling can impact many biological processes in eukaryotic cells and can regulate different cellular activities, including proliferation, differentiation, and migration, by transducing extracellular signals (Guo et al. 2022; Kent et al. 2020; Brägelmann et al. 2021).

However, to our knowledge, no preclinical or clinical research on natural products targeting MAPK-signaling pathways in cancer has been published. Therefore, this article summarizes the components of natural products and the role of the MAPK pathway in various cancers, as well as elucidating the mechanisms of their potential use for cancer treatment.

Major MAPK-signaling pathways

The three main MAPK-related-signaling pathways in cells are the classical MAPK pathway, the JNK and p38 MAPK pathway, and the ERK5 pathway.

Overactivation of the classical MAPK pathway (Ras/RAF/MEK/ERK (MAPK) pathway) leads to more than 40% of cancer cases (Yuan et al. 2020). RAS is a gene family that is commonly mutated in cancer. The most frequent mutation is KRAS, such as pancreatic ductal adenocarcinomas and colorectal carcinomas (Drosten and Barbacid 2020). RAS is usually activated on the membrane downstream of the growth factor receptors. RAS contains three gene isoforms: H-RAS, K-RAS, and N-RAS. Although they have highly homologous sequences, they have distinct functions that lead to different physiological functions (Moore et al. 2020; Yuan et al. 2020). RAF protein family kinases include three isoforms: RafA, RafB, RafC, as well as two close pseudokinases (KSR1/2). In addition, BRAF mutations occur in approximately 8% of cancers, which are very common in melanomas (Drosten and Barbacid 2020). In this classical pathway, the RAS mutation rate is the highest (22%), followed by BRAF (8%) and MEK (< 1%), while ERK mutations are sporadic (Yaeger and Corcoran 2019). The three-layered MAPK-signaling cascade is initiated when RTK and RAS are activated. The three RAF subtypes and downstream MEK1/2 and ERK1/2 from a constitute-signaling module to guide a series of physiological functions (Ullah et al. 2022).

The p38 MAPK pathway plays essential roles in signaling cascade responses. In mammals, it has four p38 kinase members: p38α, p38β, p38γ, and p38δ. The expression patterns of the upstream activator and downstream effector differ (Cheng et al. 2020). p38 MAPK is involved in regulating cell proliferation, growth, and apoptosis. It is usually activated by MKK3 and MKK6 kinases, but can also be phosphorylated through MKK4 kinase, which is an activator of JNK. When the p38 protein is activated, it is usually transferred from the cytoplasm to the nucleus to regulate downstream-signaling molecules (Sui et al. 2014). JNK has three subtypes: JNK1, JNK2, and JNK3. JNK1 and JNK2 are widely distributed in tissues, but JNK3 is mainly limited to neuronal tissues, testis, and cardiac myocytes (Cargnello and Roux 2011). They respond to various stressors, such as DNA-damaging agents and oxidative stress (** pancreatic cancer. Pancreatic cancer patients are usually categorized into resectable, marginally resectable, locally advanced, and metastatic groups according to the degree of disease. Surgical resection is currently the main treatment method. Systemic chemotherapy combinations are often administered to patients with advanced disease (Mizrahi et al. 2020).

The microenvironment of pancreatic cancer has received increasing attention and consists mainly of cancer cells, stromal cells and extracellular components (Ren et al. 2018a, b). PDAC is the most commonly observed intraepithelial tumor of the pancreas (Vincent et al. 2011). Bryant et al. (2019) suggested that PDAC characteristics include KRAS and autophagy-dependent tumor growth, demonstrating that the inhibition of KRAS and ERK could increase autophagic flow. From their data, the authors believe that a drug combination that could simultaneously inhibit ERK and upregulate the autophagy process would be a possibly effective therapeutic approach. Ravichandran et al. (2022) treated PDAC with the MEK inhibitor trimetinib. MAPK-signaling pathway inhibition resulted in decreased c-MYC expression levels and an increase in MiT/TFE-dependent lysosomal biogenesis. The destruction of ferritinophagy synergizes and cooperates with the KRAS/MAPK-signaling pathway to inhibit PDAC growth, highlighting a key target of metabolic dependency.

In another study, Lin et al. (2021) also showed that the MAPK pathway is connected to pancreatic cancer cells. PA cells were significantly inhibited when a PKC/MEK inhibitor was added to cancer cells overexpressing TRPM2. The results suggested that TRPM2 possibly directly activates PKCα through calcium or indirectly triggers PKCε and PKCδ through increased DAG. This then activates the MAPK-signaling pathway to promote PA growth.

Pancreatic cancer is frequently at an advanced stage when diagnosed (Klein 2021) and has developed chemotherapy resistance, which contributes to the unsatisfactory treatment of pancreatic cancer patients. Targeting the MAPK-signaling pathway may provide a new option for treating pancreatic cancer.

MAPK-signaling pathway in gastric cancer

Gastric cancer is a highly molecularly and phenotypically heterogeneous disease. Helicobacter pylori infection, pickled food, and smoking are all risk factors for gastric cancer (Smyth et al. 2020). Differences in tumor biology between Eastern and Western countries increase the complexity of international standard treatments. The effective ways to treat gastric cancer include systemic chemotherapy, immunotherapy, surgery, targeted therapy, and radiotherapy. Drugs approved for the treatment of gastric cancer include ramucirumab and pembrolizumab (Joshi and Badgwell 2021).

The MAPK-signaling pathway is connected with multiple factors in gastric cancer development, metastasis, and treatment. The secondary messenger Ca2+ is a crucial regulatory factor during gastric cancer metastasis. Calcium release activates the calcium regulator (ORAI2), which can enhance cancer cell metastasis by inducing FAK-mediated MAPK/ERK pathway activation (Wu et al. 2021). HDACs are a hot topic, with inhibition of HDACs being recognized as a cancer treatment method. Functional measurements showed that Class IIA (HDAC4) is upregulated in gastric cancer cells and related to poor prognosis. HDAC4 inhibits the transcription of ATG4B in an MEF2A-driven manner, prevents MEKK3 from p62-dependent autophagic degradation, and then activates p38 protein kinase. HDAC4 plays a carcinogenic role in gastric cancer. Targeted treatment focused on HDAC4 may be a new strategy (Zang et al. 2022).

One report described a new non-coding RNA, circMAPK1, that is involved in the MAPK-signaling pathway, with its expression levels decreasing in gastric cancer. However, lower circMAPK1 expression levels are associated with lower survival rates in cancer patients. In gastric cancer, circMAPK1 plays an inhibitory role by encoding the MAPK1-109aa protein, specifically by inhibiting the phosphorylation of MAPK1 by competitively combining with MEK1 and then repressing the downstream MAPK pathway. CircMAPK1 is a good predictor of gastric cancer and provides a direction for treatment (Jiang et al. 2021).

There are many studies on gastric cancer cases involving human EGFR2. For example, in a clinical phase III study for advanced HER2 cancer, adding pembrolizumab to chemotherapy and trastuzumab could significantly reduce tumor size and improve the objective remission rates (Janjigian et al. 2021). However, because of the abnormal activation of HER2 and downstream signals, such as the amplification, mutation, or upregulation of HER2, KRAS, and AKT, the sensitivity and drug resistance of patients are insufficient. Poor patient response remains a clinical challenge (Shi et al. 2021). Inhibitors of the MAPK-signaling pathway have good efficacy when combined with other drugs, but some of these drugs alone have poor efficacy. For example, the MEK1 gene can have an activation mutation that causes gastric cancer. After treatment with trametinib alone, ERK1/2 is reactivated and the cancer cells become resistant to the drug. However, when used in combination with lapatinib, ERK1/2 activation was reversed and drug resistance was eliminated. Therefore, using drugs in combination is a possible treatment method to overcome drug resistance (Mizukami et al. 2015; Wang et al. 2021a, b).The anti-cancer intervention measures that affect the targeted MAPK-signaling pathway at different stages of clinical trials are shown in Table 1.

Natural product-targeted MAPK-signaling pathway for cancer prevention and treatment

Natural products play a significant role in treating diseases, especially various cancers and contagions, and as such have elicited the attention of many researchers (Atanasov et al. 2021). The chemical composition of products from different sources has become a promising method for preventing and treating cancer. A series of natural products are related to many signaling pathways and play an anti-tumor role. For example, sulforaphane, curcumin, quercetin, and resveratrol can affect the MAPK, PI3K/Akt, NF-κB, and other pathways to regulate the growth and proliferation of cancer cells (Shakeri et al. 2021). The following sections describe some of the natural active ingredients, summarize the relevant literature on natural products targeting the MAPK-signaling pathway in cancer, present preclinical studies from the last 5 years on different cancer types, and elucidate their mechanisms of action.

Flavonoids

Flavonoids belong to plant secondary metabolites, a class of compounds with C6–C3–C6 as their basic skeleton. In plants, this is mainly bound to sugars in the form of glycosides or carboglycosyl groups, and to a lesser extent in free form (Imran et al. 2019). Among the natural products that have been discovered so far, flavonoid components have been demonstrated to have significant anti-tumor activity by numerous studies. For example, eupatilin (Wang et al. 2018a, b, c, d) is a natural flavonoid. In esophageal tumor cells, eupatilin can inhibit ERK1/2 phosphorylation and growth of the esophageal tumor cell line TE1. In trials with the endometrial cancer cell lines Hec1A and KLE, eupatilin could upregulate ERK1/2 phosphorylation and inhibit tumor cell proliferation. Compared with cisplatin, its inhibitory effect was more effective and had fewer associated toxicity and side effects. According to reports, the activity of ERK1/2 protein is also related to apoptosis of oral squamous cell carcinoma cells. Hsieh et al. (2021) found that chrysosplenol D could inhibit the activation of key target proteins in the MAPK-signaling pathway, including ERK1/2, JNK, and p38, thereby enhancing the cleaved PARP activation and mediating the arrest and apoptosis of cancer cells. Flavonoids targeting the MAPK-signaling pathway and their regulatory mechanisms are shown in Table 2 and the flavonoid structures are shown in Fig. 3.

Table 2 Detailed information of 28 flavonoids
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Fig. 3
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Structures of 28 flavonoids

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Phenols

Phenolic compounds are plant secondary metabolites that are widely found in nature. Phenolic compounds are structurally diverse and have antioxidant, anti-tumor, and antiviral effects (Almanza-Aguilera et al. 2023; Huminiecki 2022; Sorrenti et al. 2023). Phenolic compounds can regulate cancer cell apoptosis by modulating protein kinases in the MAPK-signaling pathway. Vanillin is a natural aromatic organic compound mainly found in plants, including vanilla pompon, vanilla planifolia, and vanilla tahitiensis. Vanillin can upregulate p38 phosphorylation in colorectal cancer cells and increase cancer cell apoptosis, with almost no treatment-related side effects (Li et al. 2021a, b, c). According to another study, vanillin can also inhibit the MAPKsignaling pathway, downregulate the phosphorylation of ERK, JNK, and p38 protein kinases, and reduce the number of cancer cells in colon tissues (Li et al. 2018a, b). Resveratrol is a natural phenolic compound with high anti-cancer activity and can be used to treat various cancers. According to a previous study, resveratrol can inhibit the ERK and p38 MAPK-signaling pathways by downregulating ERK and p38 phosphorylation in pancreatic cancer cells, reducing the proliferation and diffusion of cancer cells (Chen and Liu 2018). In addition, resveratrol prevents interleukin-6-induced gastric cancer metastasis by inhibiting RAF/MAPK pathway activation (Yang et al. 2018). The anti-cancer mechanisms of action of phenolic compounds are shown in Table 3 and the structures are illustrated in Fig. 4.

Table 3 Detailed information of 16 phenols
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Fig. 4
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Structures of 16 phenols

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Terpenoids

Terpenes, most of which are polymers of isoprene and their derivatives, are a widely distributed class of natural products. They are classified based on the number of isoprene units in the molecular structure, including monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes. Each isoform has different biological activities, with some having anti-cancer effects (Wei et al. 2023; Zhang et al. 2023). Zerumbone (Lv et al. 2018) is a monocyclic sesquiterpenoid compound that is isolated from the root of Zingiber Zerumbet Smith. In HepG2 liver cancer cells, zerumbone can inhibit the metastasis and proliferation of hepatoma cells in a dose-dependent manner by downregulating ERK1/2 phosphorylation and upregulating p38 phosphorylation. Jalili-Nik et al. (2021) also showed that zerumbone can suppress glioblastoma multiform cancer cell metastasis by reducing ERK1/2 phosphorylation. Oridonin is a natural tetracyclic diterpenoid compound. Oridonin may induce oral cancer cell apoptosis by the ROS-mediated p38 and JNK pathways (Oh et al. 2018). Research in colon and pancreatic cancers suggested that oridonin can significantly upregulate p38 phosphorylation and participate in cancer cell apoptosis. When using a p38-specific inhibitor (SB203580), inhibition of p38 significantly attenuated the increase in p–p53 levels induced by oridonin. These results showed that oridonin can trigger p53 signaling in cancer cells via the p38 pathway and was directly involved in cancer cell apoptosis (Liu et al. 2018; Chen and Liu 2018). The mechanisms by which terpenoids modulate the MAPK-signaling pathway are shown in Table 4 and the structures are shown in Fig. 5.

Table 4 Detailed information of 24 terpenoids
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Fig. 5
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Structures of 24 terpenoids

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Alkaloids

Alkaloids are a class of basic nitrogen-containing organic compounds found in nature, most of which have complex circular structures. Alkaloids are one of the clinically effective ingredients in the treatment of diseases (Gjorgieva Ackova et al. 2023; Guo et al. 2023). Wang et al. (2018a, b, c, d) found that evodiamine could upregulate the phosphorylation levels of p38 and JNK in glioblastoma multiforme cells, which led cancer cell apoptosis. Evodiamine also induced apoptosis in ovarian cancer cells by disrupting the mitochondrial membrane potential through activation of JNK and ERK. Zhao et al. (2021a, b) found that sophoridine significantly upregulated the phosphorylation levels of JNK, ERK, and p38, which in turn promoted macrophage M1 polarization, thereby inhibiting cancer cell growth. The anti-cancer mechanisms of action of alkaloids are shown in Table 5 and the structures are illustrated in Fig. 6.

Table 5 Detailed information of 6 alkaloids
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Fig. 6
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Structures of 6 alkaloids

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Steroidal saponins

Steroids are a wide class of chemical compounds in nature, all of which have a cyclopentano-perhydrophenanthrene parent nucleus in their structures. Certain steroidal saponins are already being used in cancer treatment studies (Bouabdallah et al. 2023; Majnooni et al. 2023). For example, timosaponin AIII is a steroid saponin that can play an anti-cancer role in different cancers, especially breast cancer. Work in MDA-MB-2 and MCF231 breast cancer cell lines suggested that timosaponin AIII could trigger DNA damage by activating p38, then indirectly cause G2/M phase arrest that reduced cell survival (Zhang et al. 2020). The mechanisms by which steroids can regulate the MAPK-signaling pathway are shown in Table 6 and their structures are shown in Fig. 7.

Table 6 Detailed information of 5 steroidal saponins
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Fig. 7
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Structures of 5 steroidal saponins

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Quinones

Quinones are natural organic compounds that contain unsaturated cyclic diketone structures and mainly include four types: benzoquinone, naphthoquinone, phenanthrenequinone, and anthraquinone. Wang et al. (2018a, b, c, d) found that juglone could induce the activation of the p38 and JNK MAPK-signaling pathways, which partly led to autophagy in HepG2 cells, G2/M cell cycle arrest, and increased apoptosis in hepatocellular carcinoma cells. In addition, Han et al. (2019) observed that shikonin not only enhanced the phosphorylation of ERK, JNK, and p38 in a time-dependent manner, but also co-induced apoptosis in SNU-407 colon cancer cells through ER stress response and mitochondrial pathways. The anti-cancer mechanisms of action of quinones are shown in Table 7 and the structures are illustrated in Fig. 8.

Table 7 Detailed information of 6 quinones
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Fig. 8
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Structures of 6 quinones

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Discussion

Recently, research on the supercritical extract of rosemary was reported and registered in a clinical trial (NCT05080920). Work in non-small cell lung cancer showed that it is used in the clinic alongside standard cancer drugs, such as cisplatin and parrolizumab. Supercritical extract of rosemary can inhibit the MAPK-signaling pathway and enhance immune anti-cancer functions. Therefore, further research into its use as an adjuvant in the treatment of non-small cell lung cancer is warranted (Bouzas et al. 2022).

Kittiwattanokhun et al. (2021) revealed that S. alata extract reduces the expression levels of MMP-3 and MMP-1353 in cells and inhibits chondrosarcoma SW1353 cell migration. These observed effects are also connected with inhibition of the MAPK-signaling pathway.

Chen et al. (2018a, b) evaluated the effects of the combined use of antrodia cinnamomea and ginger on liver cancer cells, specifically the HepG2 and Huh-7 cell lines. The results showed that antrodia cinnamomea and ginger synergistically inhibited the MAPK-signaling pathway, significantly reducing ERK and p38 phosphorylation. Their effects when combined were better than those of using antrodia cinnamomea alone. This is possibly because the coculture of antrodia cinnamomea and ginger produced new triterpenoids, which changed the active components of the original plant. This concept may provide a valuable new direction for cancer treatment development.

Various internal and external factors contribute to cancer evolution. In different types of cancer, genetic changes, dysregulated signaling pathways, and loss of internal loop homeostasis all collectively support tumor growth. Alterations to components of the MAPK-signaling pathway are often present in various cancers. It is a crucial pathway for cancer cell drug resistance and proliferation, and is becoming a potential therapeutic target.

Various protein kinases in the MAPK-signaling pathway have been used as predictive biomarkers in preclinical studies of various cancers. Many researchers have also attempted to identify effective drugs to target this pathway, some of which are in clinical trials. However, drug resistance and side effects are major problems associated with these drugs. Because of the safety of natural products, the roles of their various chemical ingredients are gradually being explored. These include chrysophanol, rhein, brasinin, fargesin, and apocynin, which have been found to potentially target the MAPK pathway and are in the development stage of preclinical trials.

However, although many single-component anti-cancer mechanisms have been reported, there are few studies on the combined treatment of the chemical components of various natural products or their use in combination with clinical anticancer drugs. According to the existing in vitro experiments, the anti-cancer effects of using a combination therapy are significantly higher than those associated with a single drug. Second, because of the limitations of clinical research, there are few natural products in the clinical trial stage. However, some of these natural products are better than the existing synthetic MAPK inhibitors in terms of safety and effectiveness. Better treatment strategies may be obtained using them as an adjuvant or routine treatment for cancer. Exploring derivatives of these natural ingredients may also be a potential way to enhance the anti-cancer capacity of the original compounds.

Conclusion

The abnormal activation of specific proteins in the MAPK-signaling pathway is an important cause of various cancers. Therefore, therapeutically intervening in this signaling pathway may be an effective tumor treatment strategy. Considering the side effects of the existing MAPK inhibitors, exploring natural product compounds provides a new direction for cancer treatment. For example, vanillin, restoratrol, curcumin, oridonim, astragaloside IV, and ursolic acid have been extensively studied and found to have good anti-cancer effects. In the future, we should focus on the development of natural medicines, as well as their use in conjunction with existing medical technologies, to enhance cancer treatment approaches.