Research Progress in the Medicine-Food Dual Use of Angelica sinensis in Digestive System Tumors

Abstract

Angelica sinensis (AS) is a widely used medicinal and culinary herb frequently considered critical in traditional prescriptions. Modern pharmacological studies have validated its beneficial effects, including nourishing, blood activation, anti-inflammatory and analgesic properties, liver and kidney protection, and tumor inhibition. Due to the lack of existing reviews on AS in treating digestive system tumors (DS-T), this study investigated the pharmacological effects of AS and its primary active components in combating DS-T from three main perspectives. First, we have summarized its mechanisms for treating various DS-T by analyzing in vitro and in vivo experimental studies. Second, we analyzed frequently used radiotherapy drugs and determined the potential of AS and its active ingredients to reduce toxicity and enhance efficacy. Additionally, AS can be integrated into both regular and medicated diets, thereby effectively preventing tumor development and facilitating post-surgery and radiotherapy recovery. In conclusion, AS exhibits potential as an anti-DS-T drug, providing a theoretical foundation for daily dietary and clinical medicinal use and offering insights for future scientific research and innovation.

Introduction

Digestive system tumors (DS-T) represent a significant global health concern. Recent research indicates that in 2023, the United States documented 1,958,310 new cancer cases and 609,820 cancer-related fatalities. Among these, 348,840 new cases and 172,010 deaths were associated with DS-T. Colorectal, pancreatic, liver, esophageal, and gastric cancers are particularly prevalent and lethal within this category. ¹ Presently, the primary therapeutic interventions for DS-T include surgery, radiotherapy, and chemotherapy. However, surgical intervention presents specific indications and notable limitations, as it is significantly influenced by factors such as tumor size, infiltration depth, and staging. ² Similarly, radiotherapy and chemotherapy are susceptible to the development of substantial drug resistance, and chemotherapy agents are associated with considerable toxic side effects, potentially leading to irreversible hepatic and renal damage.^3,4 Furthermore, while gene therapy ⁵ and immunotherapy ⁶ represent effective cancer treatment modalities, issues related to indications and economic constraints lead most patients to favor pharmacological therapies. As a result, many researchers are actively searching for anti-tumor drugs that are safe, effective and easily accessible.

Numerous studies have demonstrated that certain natural medicines and their derivatives offer distinct advantages in the treatment and prevention of tumors. These substances can significantly inhibit tumor cell proliferation and metastasis when used independently. Moreover, when combined with other anti-tumor drugs, they can reduce toxicity and enhance therapeutic efficacy. Additionally, incorporating these natural compounds into the daily diet of cancer patients may improve their prognosis.^7–9

Angelica sinensis (AS) has a long history of medicinal and culinary use, spanning over 2000 years. Ancient Chinese medical practitioners acknowledge its ability to replenish blood, regulate menstruation, relieve menstrual pain, and promote digestive health. Modern pharmacological studies have identified various active ingredients in AS, including polysaccharides, coumarins, volatile oils, and flavonoids, that contribute to its anti-inflammatory, analgesic, anti-depressant, and anti-tumor properties.^10,11 Traditionally, AS has been studied for blood deficiency and gynecological conditions; however, recent interest has emerged in its potential for treating digestive diseases. Specifically, AS has demonstrated potential in treating DS-T, inhibiting tumor growth, promoting cell apoptosis, and enhancing the effectiveness of conventional treatments like radiotherapy and chemotherapy. Additionally, the integration of AS into medicinal diets can boost immunity, reduce tumor risk, and minimize postoperative complications in cancer patients. However, limited literature is available on the systematic and targeted reports on the intervention of AS in DS-T. Therefore, in this review, we will systematically elaborate on the research progress of AS intervention in DS-T, starting with the issue based on published Chinese and foreign literature. This review will provide new ideas for the development and research of AS.

The flowchart of this review is depicted in Figure 1 .

Figure 1.

Graphical summary.

Significant Anti-Tumor Effects of AS and Derivatives

The search of databases, including PubMed, Google Scholar, ScienceDirect, and China National Knowledge Infrastructure for “Angelica sinensis” and “tumor/cancer”, revealed 425 literature reports on the anti-tumor effects of AS in the past five years. With PubMed as the primary database, the retrieved experimental literature on AS and its active ingredients directly intervening in tumors was analyzed. The analysis indicated that significantly influenced tumors included liver cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, ovarian cancer, colorectal cancer, lung cancer, bladder cancer, cervical cancer, breast cancer, melanoma, and head and neck cancer. Among them, DS-T accounted for 51.5%, and visible DS-T is the current research focus.

Furthermore, to determine the intervention effect of AS on tumors, we conducted network pharmacology analysis on AS for its multi-component, multi-target, and multi-level properties. We screened the data from the traditional Chinese medicines systems database and obtained nine active ingredients and 53 potential targets of AS. We used the Metascape database, performed the Kyoto encyclopedia of genes and genomes pathway analysis for the 53 potential targets of AS, and obtained 88 related pathways. Of these, 12 pathways were associated with tumors, including pathways in cancer, microRNAs in cancer, colorectal cancer, transcriptional misregulation in cancer, proteoglycans in cancer, pancreatic cancer, and gastric cancer ( Figure 2 ). These results suggested that AS can be used to treat tumor diseases, especially DS-T. However, the specific mechanism of action requires additional investigation.

Figure 2.

Feasibility prediction of AS intervention in cancer based on network pharmacology.

In modern pharmacology, AS has been extensively investigated as an important Chinese medicinal material that is widely used as a drug and food. It primarily contains multiple active ingredients, including polysaccharides, pyranocoumarin, volatile oils, organic acids, flavonoids, and amino acids. Its functions include anti-inflammation, analgesic, anti-depressant, anti-tumor, prevention and relief of diabetes, and liver and kidney protection. In the past few years, deep research has resulted in the discovery of new active ingredients and their functions. This has significantly expanded the scope and strengthened the theoretical support of AS application. Therefore, we must remain informed about the latest developments and identify the compounds within these components that exhibit anti-tumor properties. Which tumors can be treated respectively by these compounds? Especially what are the exact mechanisms of intervention of DS-T? Since the active ingredients in AS remain unclear, the following content will provide a phased summary of its anti-tumor active ingredients and analyze its specific mechanism of inhibiting DS-T based on published literature research. The specific mechanisms of action are illustrated in Table 1 and Figure 3 .

Figure 3.

The mechanism of action active components of AS.

Table 1.

Overview of the Study.

Polysaccharides

AS polysaccharide (ASP) is the main active component of AS and an important active component of AS water extract. ASP is a water-soluble polysaccharide primarily composed of glucose, galactose, arabinose, rhamnose, fucose, xylose, and galacturonic acid. Different types and proportions of each monosaccharide form various polysaccharide complexes, possessing diverse effects, including promoting hematopoiesis, regulating immunity, resisting inflammation, inhibiting oxidation, relieving aging, and protecting the liver.^46,47 ASP can inhibit the onset and progression of various tumors, including neuroblastoma, ⁴⁸ glioblastoma, ⁴⁹ melanoma, ⁵⁰ breast cancer, ⁵¹ and liver cancer.^12–15

Regarding the mechanism of action against DS-T, ASP can intervene in the cell cycle, proliferation, iron metabolism, and apoptosis and improve the immune microenvironment during liver cancer treatment. Dong XD et al ¹² discovered a new type of ASP in AS extract: an acidic polysaccharide composed of rhamnose, arabinose, galactose, glucose, mannose, glucuronic acid, and galacturonic acid. Through in vivo experiments, they found that this polysaccharide can block liver cancer cells in the G1 phase, thereby inhibiting tumor growth, increasing the activity of spleen lymphocytes and NK cells, improving IL-2 and TNF-α cytokine levels to regulate the tumor microenvironment, and exerting anti-tumor effects by adjusting the proportion of peripheral blood lymphocyte subsets. Cheng Y et al ¹³ isolated a polysaccharide composed of arabinose, glucose, and galactose from the AS roots. The polysaccharide has the same inhibitory effect on liver cancer in vivo; however, its mechanism of action is partially achieved by increasing the average levels of serum ferritin, IL-1, ferritin, transferrin, transferrin receptor 2, and transferrin receptor 22, and accelerating iron metabolism. Ren F et al ¹⁴ conducted a more in-depth study on the mechanism of iron metabolism intervention in liver cancer. They found that the JAK/STAT and BMP-SMAD pathways regulate iron regulatory expression through ASP. Zhao Y et al ¹⁵ successfully isolated a novel alkali-soluble AS polysaccharide (AASP) composed of arabinose, galactose, and glucose from AS. They used it for anti-tumor research and observed that AASP exhibited a significant inhibitory effect on H22 liver cancer cells, inhibiting their proliferation by blocking the cell cycle at the G0/G1 phase and regulating the immune microenvironment by stimulating immune cell proliferation.

Decursin (DE) and Decursinol

DE and Decursinol are isomers, both of which are effective compounds of AS. ⁵² A pyranocoumarin-like compound isolated from AS roots has multiple pharmacological properties, including anti-inflammation, anti-stereochemistry, anti-oxidant, and anti-tumor. ⁵³ Pharmacokinetic studies have suggested that DE and Decursinol are extensively converted into Decursinol in rodents and humans; therefore, researchers frequently select one or a combination of the two. ⁵⁴ Furthermore, DE and Decursinol can inhibit the onset and progression of various tumors, including head and neck lymphoma, ⁵⁵ B-cell lymphoma, ⁵⁶ glioblastoma, ⁵⁷ melanoma, ⁵⁸ lung cancer, ⁵⁹ breast cancer, ⁶⁰ cervical cancer, ⁶¹ prostate cancer, ⁶² pancreatic cancer, ¹⁶ gastric cancer,^17,18 and colorectal cancer.^19–21

Regarding the mechanism of inhibiting DS-T, DE and Decursinol can treat gastric, pancreatic, and colorectal cancer by interfering with cell cycle proliferation, migration, invasion, apoptosis, and autophagy. Kim S et al ¹⁷ reported that DE downregulated CXCR7 dose-dependently, inhibited the proliferation, migration, and invasion of gastric cancer, and induced cell apoptosis by mediating the STAT3/c-Myc signaling pathway. Moreover, they reported that DE can reduce cell viability dose-dependently, induce cell cycle arrest, inhibit cell growth through the CTSC-E2F3 axis, and inhibit autophagy flux by inhibiting CTSC. ¹⁸ Kweon B et al ¹⁶ extracted DE from AS by ethanol using ultra-high-performance liquid chromatography and applied it to pancreatic cancer cells. They found that DE can inhibit cell viability and colony formation. Moreover, they reported that DE can induce G0/G1 phase arrest, promote Caspase-3-dependent apoptosis by downregulating cyclin D1 and CDK4, and exert anti-metastasis effects by inhibiting the expression and activity of MMP-2 and MMP-9 by inhibiting p38 phosphorylation. Kim WJ et al ¹⁹ reported that DE can induce cell death by downregulating the anti-apoptotic factor Bcl-2 and upregulating the pro-apoptotic molecules Cytochrome c, Caspase 3, and Bax. This can result in G1 phase cell cycle arrest, inhibiting cell proliferation by reducing the expression of cyclin D1 and CDK4 expression. Ge Y et al ²⁰ investigated the mechanism of DE intervention in colorectal cancer cells in combination with the tumor microenvironment. They found that DE can promote the degradation of HIF-1α and HIF-1 in the hypoxic tumor microenvironment, inhibiting cancer cell proliferation, inducing cell apoptosis, and inhibiting cancer cell invasion under hypoxia. Regarding its specific pathway, Yang Y et al ²¹ reported that DE affects the proliferation, apoptosis, and migration of colorectal cancer cells through the PI3 K/Akt signaling pathway.

N-Butylidenephthalide (BP)

BP is a volatile oil compound isolated from AS extract, which can induce angiogenesis, protect retinal cells, and resist cancer.^63,64 BP can inhibit the onset and development of various tumors, including oral squamous cell carcinoma, ⁶⁵ glioblastoma multiforme, ⁶⁶ breast cancer, ⁶⁷ ovarian cancer, ⁶⁸ bladder cancer, ⁶⁹ prostate cancer, ⁷⁰ lung cancer, ⁷¹ gastric cancer, ²² liver cancer,^23,24 and colorectal cancer. ²⁵

Regarding the mechanism of resisting DS-T, BP can intervene in the cell cycle, proliferation, migration, invasion, apoptosis, and EMT in treating gastric, liver, and colorectal cancer. Liao KF et al ²² validated the therapeutic effect of BP on gastric cancer through in vitro, in vivo, and clinical experiments. The clinical trials revealed that the survival rate of gastric cancer patients significantly improved after consuming AS. In vitro and in vivo experiments indicated that BP can inhibit the proliferation of gastric cancer cells, induce gastric cancer cell apoptosis through the mitochondrial apoptosis pathway, inhibit gastric cancer growth by increasing REDD1 expression and inhibiting the mTOR signaling pathway, and inhibit gastric cancer cell migration and invasion by regulating EMT. Chen YL et al ²³ studied the therapeutic effect of BP on liver cancer and found that BP can induce Nur77 to migrate from the nucleus to the cytoplasm, resulting in Cytochrome c release and Caspase-3-dependent apoptosis. Besides, they found that the CREB pathway is partially involved in BP-induced tumor apoptosis. However, due to its unstable structure, its potential anti-tumor activity has been reduced. Chang KF et al^24,25 reported that BP has higher cellular uptake and cytotoxicity when encapsulated in Lipolyplexs: LPPC. By intervening in colorectal cancer, it was found that BP/LPPC induces cell cycle arrest in the G0/G1 phase by altering the levels of cell cycle regulatory factor CDK4/Cyclin D1 and activates cell apoptosis through FasL/Fas/Caspase-8 external and Bax/Caspase-9 internal pathways. By intervening in liver cancer, BP/LPPC blocks the cell cycle in the G0/G1 phase by increasing the expression of cell cycle regulatory factors p53, phospho-p53, and p21. Furthermore, it reduces the expression of cell cycle-related proteins Rb, phospho-Rb, CDK4, and cyclin D1, induces cell apoptosis by activating exogenous Fas-L and Caspase-8 and intrinsic Bax and Caspase-9 apoptotic pathways, and activates the caspase cascade reaction to trigger HCC cell death. Furthermore, they investigated the effect of BP/LPPC on breast cancer, ⁷² melanoma, ⁷³ and other tumors and found that BP's anti-tumor effect has significantly improved, which will significantly expand the scope and enhance the quality of the BP curative effect.

Ferulic Acid (FA)

FA is a phenolic organic compound extracted from AS, which has various effects, including anti-inflammation, analgesic, anti-radiation, immune enhancement, and anti-tumor.^74,75 FA can inhibit the occurrence and progress of a variety of tumors, including lung cancer,^76,77 osteosarcoma, ⁷⁸ cervical cancer, ⁷⁹ prostate cancer, ⁸⁰ gastric cancer,^26,27 pancreatic cancer, ²⁸ esophageal cancer, ²⁹ liver cancer, ³⁰ and colorectal cancer.^31,32

In terms of resisting the DS-T mechanism, FA can act in the treatment of gastric cancer, liver cancer, esophageal cancer, pancreatic cancer, and colorectal cancer by interfering with cell proliferation, migration, invasion, apoptosis, autophagy, and angiogenesis. Niu YX et al ²⁶ demonstrated that FA can induce apoptosis in gastric cancer SGC-7901 cells by upregulating the expression of COX-2, survivin, XIAP, and p53 mRNA and proteins. Zhang Y et al ²⁷ found in their study on the proliferation of gastric cancer MGC-803 cells that FA upregulates the mRNA and protein expression of Bax and downregulates the mRNA and protein expression of Bcl-2 to induce gastric cancer apoptosis and achieve the effect of inhibiting its proliferation. Fahrioğlu U et al ²⁸ observed that FA can affect the cell cycle and inhibit cell proliferation by upregulating the expression of p53 in pancreatic cancer cells, downregulating the expression of cyclin D1 and CDK4/6, and inhibiting cell invasion and migration by reducing colony formation. Cao Y et al ²⁹ reported that FA can reduce cell viability and colony-forming ability to inhibit esophageal cancer cells’ migration and invasion by inhibiting angiogenesis. It can still increase MDA content, ROS production, iron load, the release of lactate dehydrogenase, activation of Caspase-3, and induce cell apoptosis. Ezhuthupurakkal PB et al ³⁰ combined zinc oxide nanoparticles with FA to intervene in liver cancer and found that this complex can induce oxidative DNA damage and cell apoptosis by inducing ROS production. In addition, Sawata Y et al ³¹ found that binding FA with resveratrol can produce a new complex that can inhibit the proliferation of colon cancer HCT116 cells by increasing the mRNA level of tumor suppressor p15, a CDK inhibitor. For the signaling pathway, Chen S et al ³² found that FA induces autophagy and apoptosis in colon cancer CT26 cells through the MAPK signaling pathway

Imperatorin (IMP)

IMP is a natural furacoumarin compound isolated from AS. It has various pharmacological activities, including anti-inflammation, anti-oxidant, cardiovascular toxicity prevention, and anti-tumor effects.^81,82 IMP can inhibit the occurrence and progress of a variety of tumors, including osteosarcoma, ⁸³ lung cancer, ⁸⁴ breast cancer, ⁸⁵ melanoma, ⁸⁶ esophageal cancer, ³³ liver cancer, ³⁴ and colon cancer.^35,36

Regarding the mechanism of action against DS-T, IMP can act on the treatment of esophageal, liver, and colon cancer by intervening in the cell cycle, proliferation, metastasis, apoptosis, and angiogenesis. Xu WW et al ³³ found that IMP has a significant effect on inhibiting tumor metastasis. Therefore, using esophageal cancer as a research model, they studied the mechanism of IMP's anti-metastasis effect and found that IMP can inhibit the TGF β 2-ERK signal axis to suppress esophageal cancer metastasis. Li X et al ³⁴ reported that IMP can synergistically trigger Bax translocation and Bak activation to promote liver cancer cell apoptosis by inducing Mcl-1 degradation, thereby inhibiting liver cancer. Mi CL et al ³⁵ found that IMP can inhibit HIF-1α protein synthesis by downregulating mTOR/p70S6 K/4E-BP1 and MAPK pathways to inhibit the proliferation and angiogenesis of human colon cancer cells. Zheng YM et al ³⁶ found that IMP induces cell cycle arrest in the G1 phase and induces apoptosis in colon cancer cells by upregulating the p53 and caspase cascade.

4-Hydroxyderricin (4-HD)

4-HD is a natural flavonoid compound extracted from AS, which has multiple pharmacological effects of anti-inflammation, anti-oxidant, anti-diabetes, lipid regulation, and prevention of muscle atrophy.^87–90 4-HD can inhibit the onset and progression of various tumors, including osteosarcoma, ⁹¹ melanoma, ⁹² gastric cancer, ³⁷ and liver cancer. ³⁸

Regarding the mechanism of action against DS-T, 4-HD can intervene in cell proliferation, metastasis, and apoptosis in treating gastric and liver cancer. The overexpression of EPRS seriously affects the development of gastric cancer. Liu H et al ³⁷ found that 4-HD can directly bind to EPRS and block the WNT/GSK-3 β/β- catenin signaling pathway to inhibit the proliferation of gastric cancer. Gao X et al ³⁸ reported that 4-HD can mediate cell apoptosis and cell cycle arrest through the PI3 K/AKT/mTOR signaling pathway and inhibits the proliferation and metastasis of liver cancer.

Isoimportation (IIMP)

IIMP is a kind of furocoumarin compound extracted from AS, which has effects like anti-inflammation, analgesic, antiviral, anti-diabetes, anti-osteoporosis, and anti-tumor.^93–96 IIMP can inhibit the occurrence and progress of various tumors, including nasopharyngeal carcinoma, ⁹⁷ gastric cancer,^39,40 liver cancer, and colorectal cancer. ⁴¹

Regarding the mechanism of action against DS-T, IIMP can intervene in cell cycle proliferation, metastasis, apoptosis, and epithelial-mesenchymal transition (EMT) in treating gastric, liver, and colorectal cancer. Tong K et al ³⁹ reported that IIMP induces apoptosis in gastric cancer cells by increasing the expression levels of pro-apoptotic proteins Bax, cleaved-caspase-3, and cleaved-caspase-9 and decreasing the expression levels of anti-apoptotic proteins Survivin and Bcl-2, thereby inhibiting tumor growth in vitro and in vivo. Furthermore, Yang HB et al ⁴⁰ found that IIMP can inhibit the proliferation of gastric cancer by blocking gastric cancer cells at the G2/M phase in the cell cycle. Kim NY et al ⁴¹ found that IIMP can inhibit NF-κ B activation and CXCR4 expression in liver and colorectal cancer cells to inhibit EMT and metastasis processes.

Picrasidine Q (PQ)

PQ is an alkaloid compound extracted from AS. In terms of the mechanism of action against DS-T, PQ can intervene in cell proliferation and apoptosis in treating esophageal cancer by inhibiting the AKT/mTOR signaling pathway and directly acting on FGFR2, thereby inhibiting the cell growth of KYSE30 and KYSE410 ESCC cells and inducing cell apoptosis. ⁴²

Oxypeucedanin (OPD)

OPD is a furocoumarin compound extracted from AS, which has effective pharmacological properties, including anti-proliferation, cytotoxicity, anti-influenza, and anti-allergy. ⁹⁸ OPD can inhibit the onset and development of various tumors, including prostate cancer, ⁹⁹ melanoma, ¹⁰⁰ and liver cancer. Regarding the mechanism of action against DS-T, OPD primarily intervenes in treating liver cancer by intervening in the cell cycle and proliferation. Park SH et al ⁴³ found that OPD induced G2/M phase cell cycle arrest and upregulation of the p53/MDM2/p21 axis to inhibit the proliferation of liver cancer cells.

AS Crude Extract

In addition to the well-established anti-tumor components previously mentioned, multiple studies have yet to specifically investigate and differentiate the individual components responsible for their effects. Most researchers have used AS as a whole to investigate the intervention effect of AS crude extract on tumors and achieved significant results. Zhao B et al ⁴⁴ intervened with AS extract in a mouse model of colorectal cancer induced by Azoxyethane/Dxtran sodium sulfate (AOM/DSS). They found that the reduction of DNA damage, 8-oxoguanine, and γ- H2AX were effective at all stages of tumor formation. Peng Y et al ⁴⁵ used AS phenolic acid and AS supercritical extract to intervene in a mouse model of colorectal cancer induced by AOM/DSS. They observed that in the early stage of tumor formation, AS phenolic acid and AS supercritical extract could reduce DNA damage caused by AOM/DSS, reduce inflammation in the later stage, mediate immune response, therefore inhibit tumor cell proliferation, and intervene in the onset and progression of colorectal cancer.

Others

In recent research, certain active ingredients have been identified to be effective against tumors; however, their efficacy in DS-T remains uncertain. Angelicin can play an anti-tumor role in breast cancer, ¹⁰¹ lung cancer, ¹⁰² and other tumors due to its medical properties, including pro-apoptotic, anti-proliferation, and anti-metastasis activities. Chalcones and xanthoangelol can inhibit melanoma development by directly intervening with BRAFV600E and PI3 K. Moreover, it can also result in cell cycle arrest and apoptosis by blocking the activation of downstream signaling pathways. ¹⁰² Xanthol regulates cell cycle arrest, apoptosis, and EMT-related genes by downregulating the PI3K-AKT signaling pathway, inhibiting NSCLC proliferation and metastasis. ¹⁰³ Ligustilide can inhibit the promotion of non-small cell lung cancer through glycolic metabolism. ¹⁰⁴ It can induce c-Myc-dependent cell apoptosis by activating endoplasmic reticulum stress signals and inhibiting oral cancer cells. ¹⁰⁵ Cis khellactone, isolated from the chloroform soluble part of AS rhizome, can induce three types of programmed cell death (PCD): cell apoptosis, autophagy-mediated cell death, and necrotic apoptosis, which has been confirmed on 18 different cancer cells. ¹⁰⁶

Synergistic and Detoxifying Effects of aS and its Derivatives

In Chemotherapy

Chemotherapy is the standard first-line treatment for tumors. The National Comprehensive Cancer Network guidelines recommend that patients select platinum-based or fluorouracil-based drugs for chemotherapy. ¹⁰⁷ However, most of these anti-tumor drugs have drawbacks, including non-significant effects or significant side effects. ⁴ Consequently, it is imperative to identify synergistic drugs that can reduce conventional chemotherapy drugs’ dosage or their toxicity and side effects. The combination of Chinese herbal medicine and Western medicine can be a new way to improve efficacy and alleviate cancer-associated side effects. ¹⁰⁸ Besides, recent research has found that AS can improve the sensitivity of radiotherapy and chemotherapy with reduced side effects. ¹⁰⁹

The multiple drug resistance of tumors is an important factor affecting the success rate of tumor chemotherapy. Research has found that IMP significantly inhibits the multiple drug resistance produced by taxol and doxorubicin (DOX). ¹¹⁰ FA can reduce the resistance of tumor cells to paclitaxel and induce apoptosis of paclitaxel-resistant cells by upregulating the expression of apoptotic proteins. ¹¹¹ Additionally, FA regulates P-glycoprotein-mediated multidrug resistance, promotes apoptosis signaling in Dox-induced drug-resistant cells, and resists P-glycoprotein expression by inhibiting PI3 K/Akt/NF- κ B signaling pathway. ¹¹²

Cisplatin (DDP) is the first-generation platinum-based chemotherapy drug widely used to treat various solid cancers. It can inhibit the DNA replication process of cancer cells, resulting in cell apoptosis. Moreover, it has significant inhibitory effects on various tumors. ¹¹³ However, it has significant nephrotoxicity, which is extremely limited in its dosage during use. Chiu SC et al ⁶⁹ investigated whether BP can enhance the therapeutic effect of DDP and other chemotherapy drugs in combined treatment. They treated bladder cancer cells with DDP or BP or a combination of both and found that bladder cancer cells treated with BP exhibited increased sensitivity to DDP. Furthermore, Hu JJ et al ¹¹⁴ observed that the active ingredient imperatorin of AS can be used as a DDP sensitizer by downregulating the expression of Mcl-1 during HCC chemotherapy. Furthermore, the combined use can better induce apoptosis of liver cancer cells.

Oxaliplatin (OXA), a third-generation platinum-based anti-tumor drug, significantly inhibits local tumors. ¹¹⁵ Compared with DDP, it has stronger efficacy and can be better tolerated. However, OXA has more significant side effects, including peripheral neurotoxicity. The incidence of peripheral neurotoxicity is higher than that of DDP. Hao D et al ¹¹⁶ investigated the intervention of AS supercritical liquid extract combined with OXA in colorectal cancer to identify drugs that can increase the efficacy of OXA or reduce its toxic side effects. In vitro experiments indicated that the combination of drugs can inhibit the proliferation and metastasis of colon cancer. In vivo experiments were consistent with in vitro experiments, suggesting they can effectively reduce tumor volume, growth rate, and metastasis rate. Tan Y et al, ¹¹⁷ performed meta-analysis and sensitivity analysis and reported that AS can improve the response of OXA chemotherapy to AGC tumors, which has been proven in multiple experimental studies to help improve tumor response. Zhang XL et al ¹¹⁸ found that FA can significantly increase the sensitivity of drug-resistant HCT116 colorectal cancer cells to OXA. In addition, they demonstrated that FA increased GM3 levels and reduced Gb3 and P-gp levels by inhibiting NEU3 expression, thereby increasing the chemotherapy sensitivity of drug-resistant HCT-116/L cells to OXA.

5-Fluorouracil (5-FU) is a first-line anti-tumor drug that exhibits significant anti-tumor activity due to its ability to regulate thymidylate synthase activity and reduce DNA and RNA synthesis. However, due to the development of drug resistance and adverse side effects after higher doses of treatment, its clinical application is limited. Chang KF et al ²⁵ found that combining BP and 5-FU can synergistically inhibit the growth of colorectal cancer HT-29 cells.

Carmustine (BCNU) is a type of chemotherapy drug. It works by interfering with DNA in cancer cells, preventing them from dividing into two new cells and inhibiting tumor growth. It is frequently used to treat brain, lymphatic, and liver cancers. However, it reduces the number of platelets and white blood cells in the blood, increasing the risk of infection and complications, including bleeding. Yu YL et al ¹¹⁹ observed that in treating liver cancer, the combination of BP and BCNU can significantly enhance the intervention effect of BCNU on DNA and increase its anti-tumor proliferation effect.

One of the effective chemotherapy modalities is the combined use of defective HR pathways and PARP inhibitors. Choi YE et al ¹²⁰ synergically intervened with ferulic acid and PARP inhibitors in breast cancer cells. They found that FA can inhibit DNA damage repair and increase the sensitivity of breast cancer cells to PARP inhibitors.

Diosburgin-B (DB) is a highly effective anti-tumor drug; however, hepatotoxicity limits its clinical dosage and application range. A study reported that AS polysaccharides can prevent acetaminophen-induced acute liver injury and cell death by inhibiting oxidative stress and cell apoptosis in vitro and in vivo. This suggests that AS polysaccharides can be a potential intervention to reduce liver toxicity. ¹²¹ Therefore, Li CF et al ¹²² validated it by treating liver cells with ASP, DB, or ASP combined with DB. They observed that ASP can eliminate cell cycle arrest caused by high-dose DB by upregulating cyclin D1 and CDK2. Besides, it can inhibit high-dose DB-induced liver cell apoptosis and autophagy by activating the MEK/ERK pathway.

DOX has been extensively used as a chemotherapy agent to treat various types of cancer; however, it can have toxic effects on the brain. Furan coumarins have good preventive and therapeutic effects on cardiovascular and brain diseases. Therefore, studies have been performed on the protective effects of furan coumarin compounds IIMP and OPD on DOX-induced brain toxicity. They have found that IIMP and OPD can reduce DOX-induced cell apoptosis by inhibiting ROS production. ¹²³

Radiotherapy

In addition to chemotherapy, the combination of radiation therapy and radiosensitizers is one of the most effective methods for treating tumors. It has been reported that cancer cells are most sensitive to radiation during the G2/M phase of the cell cycle. The G2/M arrest is the primary cause of anti-tumor or radiation sensitizer-induced cell death. ¹²⁴ Su YJ et al ⁶⁷ found that BP promotes mitochondrial-mediated apoptosis and inhibits the metastatic activity of breast cancer cells. Additionally, it can induce G2/M stagnancy in human breast cancer cells, increasing the radiosensitivity. Ligustalit can increase the onset of DNA damage in oral cancer cells after radiation therapy and has the potential as a radiation sensitizer. ¹⁰⁵ Furthermore, studies have suggested that AS and Red Ginseng extracts can enhance cell apoptosis induced by 12C6 + heavy ion radiation, specifically by downregulating survivin protein expression to enhance Caspase-9 protein expression and cause cell apoptosis.^125,126

Preventive and Therapeutic Effects of AS and its Derivatives on Radiotherapy, Chemotherapy, and Postoperative Complications

Although radiotherapy and chemotherapy can improve the survival rate of tumor patients, they are often accompanied by a series of complications, including cardiotoxicity, muscle atrophy, hepatotoxicity, lymphedema, constipation, anemia, and immune deficiency. These complications adversely affect the quality of life of tumor patients. Therefore, for cancer patients, the prevention and treatment of complications after radiotherapy and chemotherapy are equally important. Recently, multiple studies have indicated that certain natural herbs can fight against complications associated with radiotherapy and chemotherapy, improve immunity, and do not affect the anti-tumor activity of treatment.^127,128 AS is among the most frequently used Chinese herbal medicines. ¹²⁹ Consequently, we must have a general understanding of the components and mechanisms of anti-tumor complications in AS.

Cardiac toxicity is a serious complication after cancer radiotherapy and chemotherapy. It is the second leading cause of morbidity and mortality among cancer survivors. The current chemotherapy drugs, including anthracyclines, as well as oxidative stress and matrix remodeling caused by radiotherapy, will all induce cardiac toxicity.^130–133 AS and its related compounds can reduce cardiac toxicity caused by radiotherapy and chemotherapy through anti-oxidant stress, anti-inflammation, relieving ER stress, regulating cell apoptosis and autophagy, and improving myocardial energy metabolism.^134,135 Ma C et al ¹³⁶ observed that ultrafiltration extract of radix AS and radix hedysari can reduce the proliferation of myocardial fibroblasts induced by low-dose x-ray radiation and accelerate their apoptosis, thereby reducing radiation-induced cardiac toxicity. The ultrafiltration extracts of AS and Coptis chinensis also exhibited the same effect.

Muscle atrophy is the most prominent phenotypic feature of cancer cachexia. Chen L et al ²⁶ reported that the primary active ingredient of AS, imperatorin, can alleviate cancer cachexia and prevent muscle atrophy by directly inhibiting STAT3. Kweon M et al ¹³⁷ observed that oral administration of ethanol extract from AS can alleviate muscle atrophy damage and downregulate the mRNA level of muscle-specific ubiquitin-E3 ligase. Additional research revealed that 4-hydroxydricin could overcome muscle atrophy by reducing the degradation of myosin heavy chain and myogenesis of C2C12 myoblast.

Bone marrow suppression is the primary adverse reaction of chemotherapy, which can decrease the production of red blood cells, white blood cells, and platelets in the bone marrow. ¹³⁸ Kang M et al ¹³⁹ used AS extract to intervene in cyclophosphamide-induced bone marrow suppression. They observed that AS extract can increase the levels of red blood cells and platelets in peripheral blood and inhibit thymus and spleen atrophy, contributing to the recovery from bone marrow suppression symptoms. Xiao H et al ¹⁴⁰ suggested that the decreased self-renewal ability and premature aging of hematopoietic stem cells are the primary causes of bone marrow suppression. Using ASP to intervene in 5-FU-induced bone marrow suppression, it was observed that ASP could reduce oxidative damage of hematopoietic stem cells, prevent premature aging, and improve hematopoietic function to alleviate chemotherapy-induced bone marrow suppression.

Research on AS-Related Compound Prescriptions

The crude extracts and active ingredients of AS have significant efficacy in DS-T. The available literature on its clinical application revealed that Danggui Buxue Decoction, Danggui Liuhuang Decoction, and Danggui Sini Decoction are more frequent clinical AS-related compounds, which are extensively used in the treatment of DS-T and their complications. Especially in treating gastric, esophageal, and colorectal cancer, it can improve patients’ clinical symptoms, reduce adverse reactions, improve the quality of life, and increase the effectiveness and reduce toxicity.

Clinically, considering the specificity of the tumor, AS-related compound formulas are frequently combined with radiotherapy and chemotherapy. AS-related compounds have exhibited excellent efficacy, whether it is an adjuvant FOLFOX4 regimen, ¹⁴¹ mFOLFOX6 regimen,^142,143 or combined with chemotherapeutic agents gemcitabine ¹⁴⁴ and OXA. ¹⁴⁵ It can increase the therapeutic efficacy and reduce the incidence of its adverse effects, including gastrointestinal reactions, ¹⁴⁵ neurotoxicity, ¹⁴⁶ and myelosuppression. ¹⁴⁷ It can have a good therapeutic effect in the postoperative period, radiotherapy, and chemotherapy complications, including fever, ¹⁴⁸ night sweats, ¹⁴⁹ and anemia. ¹⁵⁰ Furthermore, certain trials tested liver and kidney function and revealed that the compound had no safety risks and guaranteed safety during chemotherapy to a certain extent. ¹⁵¹ Moreover, the preoperative regimen of Renshen Danggui Huangqi Decoction can relieve postoperative insulin resistance. ¹⁵² Combining the Danggui Sini Decoction with the ion-introduction method can more effectively leverage the efficacy of Chinese medicines. ¹⁴⁶ The above results suggest that AS-related compounds have significant efficacy in the clinical treatment of DS-T and confirm that the combination of traditional Chinese medicine and chemoradiotherapy drugs has great potential in the future.

Study on AS-Related Tonic Diet

As a medical method that has lasted for more than 2000 years, Chinese medicine has developed an excellent herb use system. This system is particularly effective in combining natural drugs with daily diets to form tonic diets, which not only maintain the flavor of food but also fulfill the role of drugs. AS, as a natural herb used in food and prescriptions, has received the attention of physicians in past dynasties and has been incorporated into several relative prescriptions. Modern research has found that AS has been extensively used in DS-T treatment by acting on cancer markers, promoting the body's resistance to cancer, enhancing treatment effectiveness, and reducing side effects. ¹⁵³

Wang Q et al ¹⁵⁴ observed 80 cases of cancer-related fatigue patients with qi and blood deficiency syndrome and administered Dang Gui Bu Xue Zhou as a dietary adjuvant treatment. They reported that Dang Gui Bu Xue Zhou has the potential to significantly improve the symptoms of cognitive, emotional, and physical fatigue of cancer-related fatigue patients with qi and blood deficiency syndrome. In addition, the objective monitoring indicators indicated that Dang Gui Bu Xue Zhou had a certain regulatory effect on the hemoglobin index, white blood cell index, and red blood cell index in the blood. Li Q et al ¹⁵⁵ observed 6 cases of liver cancer, 14 cases of colon cancer, 10 cases of breast cancer, 5 cases of stomach cancer, 3 cases of lung cancer, and 2 other cases by adding He Tao Ren Gao to the nursing of tumor patients. They observed that adding food therapy to the nursing of tumor patients in traditional Chinese medicine as an auxiliary treatment significantly affects the quality of nursing. It is significant in helping patients’ physical recovery, disease treatment, and prognosis. Furthermore, Wu G et al ¹⁵⁶ their Dang Gui Sheng Jiang Yang Rou Tang research reported that it is a classic formula for medicine and food. It can play a role in warming the middle and tonifying the deficiency. Moreover, it has a high application value in treating malnutrition in tumor patients in the later stage. Qu D et al ¹⁵⁷ gave 76 tumor chemotherapy patients Qi Xue Tong Bu Zhou as an auxiliary treatment. They observed that Chinese medicine diet therapy nursing can alleviate the gastrointestinal reaction of tumor chemotherapy patients. Moreover, Ba Zhen Ji Tang and Gui Shen Dun Ji are recommended as recipes for tumor dietary therapy in traditional Chinese medicine. The composition of the related medicinal diet is provided in Table 2 .

Table 2.

Medicated Diet Prescriptions.

Prescription	Materials	Preparation	Effect
Dang Gui Bu Xue Zhou	10 g of AS, 30 g of Astragalus membranaceus, 100 g of japonica or glutinous rice, and an appropriate amount of brown sugar.	Slice AS and Astragalus membranaceus, stew them in water for 30 min, remove the dregs from the potion, cook porridge with japonica rice in casserol, and mix them with a suitable amount of brown sugar.	It tonifies qi and nourishes blood, suitable for cancer-related fatigue patients with Qi and blood deficiency syndrome.
He Tao Ren Gao	25 g of cohosh, 25 g of AS, 12 g of raw Rehmannia glutinosa, 12 g of cooked Rehmannia glutinosa, 5 g of roasted licorice, and 3 g of safflower.	Boil the medicine with water to produce the potion used later. Mix 450 g of glutinous rice flour, 450 g of buckwheat flour, 45 g of walnut kernel flour, and 450 mL of the above potion to make a dough. Coat vegetable oil and white granulated sugar on it and steam it to make He Tao Ren Gao	It regulates qi and blood and supports positive qi, making it suitable for nursing tumors in the liver, lung, stomach, breast, and colon.
Dang Gui Sheng Jiang Yang Rou Tang	9 g of AS, 15 g of ginger, and 50 g of lamb.	Stew the herb above with 800 mL water and keep the volume of the final potion at about 300 mL.	It warms the body and nourishes the deficiency, suitable for late-stage malnutrition and insufficient labor in cancer patients.
Bu Qi Yang Xue Zhou	30 g of Astragalus membranaceus and 6 g of AS.	Grind the herbs and dissolve the powder in 70 °C warm water of 50 mL, adding which porridge to eat.	Nourishing Qi and blood. It is suitable for cancer-related fatigue patients with Qi and blood deficiency syndrome.
Ba Zhen Ji Tang	1000 g of hen meat, 6 g of AS, radix paeoniae alba, Radix rehmanniae, Ligusticum wallichii and Atractylodes macrocephala, licorice, 10 g of Codonopsis pilosula, Poria cocos, three pieces of ginger, and an appropriate amount of seasoning.	Wash the chicken, cut it into pieces, place it in an earthen pot, add ginger, the herbs prepared (mounted in cloth bags), and an appropriate amount of water. Boil it over high heat, then simmer over medium heat until the chicken is cooked. Remove the herb bag, and add salt, pepper, and monosodium glutamate.	Tonifying Qi and blood. It suits tumor patients with decreased red and white blood cells after surgery, radiotherapy, and chemotherapy. The syndromes of the patients include a pale complexion, dry throat, dry mouth, wheezing when moving, palpitations, and insomnia.
Gui Shen Dun Ji	500 g of hen meat, 10 g of AS, and 10 g of Panax notoginseng.	Wash the chicken, cut it into pieces, place it in an earthen pot, add ginger, the herbs prepared (mounted in cloth bags), and an appropriate amount of water. Boil it over high heat, then simmer over medium heat until the chicken is cooked. Remove the herb bag, and add salt, pepper, and monosodium glutamate.	Promoting blood circulation and nourishing blood is suitable for tumor patients with blood stasis, which may cause subcostal or local hard lumps and fixed pain. The patients often exhibit a purple and dark tongue and thin and uneven pulse.
Qi Xue Tong Bu Zhou	8 g of Atractylodes macrocephala, 12 g of Codonopsis pilosula, 15 g of Poria cocos, 10 g of prepared rehmannia root, 20 g arrowhead mushrooms, 12 g whole AS, 150 g japonica rice, with a little white sugar added.	Boil the herb in water twice to 300 mL and take it as one dose.	It is suitable for patients with both qi and blood deficiency and gastrointestinal reactions after chemotherapy.

Summary and Outlook

Among the active ingredients of AS, AS polysaccharide, decursin, N-butylidenephthalide, ferulic acid, imperatorin, 4-hydroxypyridin, isoisomerin, picrasidine Q, and oxypulceranin significantly resist tumor in DS-T. It regulates key genes through the JAK/STAT pathway, mTOR signaling pathway, MAPK signaling pathway, PI3 K/Akt/mTOR signaling pathway, WNT/GSK-3β/β-catenin pathway, iron death, and other pathways. Besides, it plays an important role in esophageal cancer, liver cancer, pancreatic cancer, gastric cancer, colorectal cancer, and other DS-T. In terms of reducing toxicity and enhancing efficacy, these active ingredients reduce the multiple drug resistance of chemotherapy drugs and reduce the toxic side effects of drugs, including DDP, OXA, 5-FU, BCNU, DB, and DOX. Collaborative use can enhance the sensitivity of cells to chemotherapy drugs, thereby achieving a synergistic effect. Furthermore, certain active ingredients can kill tumor cells in combination with NK cells, affecting tumor formation from an immune perspective. AS is a frequently used drug with significant therapeutic effects in the chemotherapy process. Additionally, it reduces the complications after radiotherapy and chemotherapy, including cardiac toxicity, muscle atrophy, and bone marrow suppression. In addition to addressing the more intricate changes in the disease, adding this substance to a compound formula can also produce synergistic effects by combining a variety of traditional Chinese medications. AS-related Tonic Diet is capable of acting as a drug therapy for the deficiency of qi and blood, fatigue, blood stasis, and gastrointestinal reactions in the late stage of the tumor or after radiotherapy and chemotherapy.

Furthermore, AS possesses distinct advantages over other traditional herbs. Due to its rich composition of active ingredients, AS exhibits a wide range of pharmacological effects. In the context of treating DS-T, AS not only induces apoptosis through both endogenous and exogenous pathways, but it also replenishes nutrients depleted by tumors through its amino acids, volatile oils, and vitamins. This dual functionality enhances the value of AS, making it highly significant not only in traditional Chinese medicine but also in the food industry. AS can be used as a daily diet to maintain health and compensate for the deficiencies of conventional medications. Their flavor is more palatable than that of acrid potions.

In conclusion, the research of AS in the direction of DS-T is very extensive; however, it is limited to a single medicine and its active ingredients. Moreover, its relative compound medicine and tonic diet have positive therapeutic and auxiliary effects on tumor patients. In recent years, research about AS has been excessively independent, and there has been a lack of theoretical review. Consequently, this review comprehensively analyzes the anti-digestive tract tumor effect of AS from three distinct perspectives: active ingredients, compound medicine, and a tonic diet for AS. It also introduces novel treatment methods for DS-T. In future research, we propose to investigate the pharmacological effects of AS through comprehensive serum chemistry and pharmacokinetic studies. This will enable us to identify the components that enter the bloodstream and examine the dynamic alterations of these primary components following their entry into the body. Subsequently, we aim to explore the core targets and molecular mechanisms of AS in the treatment of various DS-T. This will be achieved by employing advanced methodologies such as network pharmacology and Mendelian randomization. This was followed by validation through the construction of an immune prognostic model, in vitro and in vivo experiments, and the application of multi-omics techniques. These efforts aiming to establish a scientific foundation for the clinical application of AS in treating DS-T. Clinically, the development of more AS-related diets to prevent DS-T may have a broader prospect under the premise of determining the dose's safety.