Guo-Qing Chen,Yi Nan,Shi-Cong Huang,Na Ning,Yu-Hua Du,Dou-Dou Lu,Ya-Ting Yang,Fan-Di Meng,Ling Yuan

Guo-Qing Chen,Shi-Cong Huang,Na Ning,Yu-Hua Du,Ling Yuan,College of Pharmacy,Ningxia Medical College,Yinchuan 750004,Ningxia Hui Autonomous Region,China

Yi Nan,Key Laboratory of Ningxia Ethnomedicine Modernization,Ministry of Education,Ningxia Medical University,Yinchuan 750004,Ningxia Hui Autonomous Region,China

Yi Nan,Ya-Ting Yang,Fan-Di Meng,Traditional Chinese Medicine College,Ningxia Medical University,Yinchuan 750004,Ningxia Hui Autonomous Region,China

Dou-Dou Lu,School of Clinical Medicine College,Ningxia Medical University,Yinchuan 750004,Ningxia Hui Autonomous Region,China

Abstract

Cancer seriously endangers human health.Gastrointestinal cancer is the most common and major malignant tumor,and its morbidity and mortality are gradually increasing.Although there are effective treatments such as radiotherapy and chemotherapy for gastrointestinal tumors,they are often accompanied by serious side effects.According to the traditional Chinese medicine and food homology theory,many materials are both food and medicine.Moreover,food is just as capable of preventing and treating diseases as medicine.Medicine and food homologous herbs not only have excellent pharmacological effects and activities but also have few side effects.As a typical medicinal herb with both medicinal and edible uses,some components of ginger have been shown to have good efficacy and safety against cancer.A mass of evidence has also shown that ginger has anti-tumor effects on digestive tract cancers (such as gastric cancer,colorectal cancer,liver cancer,laryngeal cancer,and pancreatic cancer) through a variety of pathways.The aim of this study is to investigate the mechanisms of action of the main components of ginger and their potential clinical applications in treating gastrointestinal tumors.

Key Words: Ginger; Medicine and food homology; Gastrointestinal cancer; Molecular mechanism; Tumor

INTRODUCTION

Cancer is a significant global health threat,with incidence and mortality rates on the rise.It poses a serious challenge to human health worldwide[1].According to recent data,there were approximately 19.3 million new cases of cancer worldwide in 2020,resulting in 10 million deaths.Gastrointestinal cancer stands out as one of the primary causes of mortality[2].Out of the top 10 cancers,gastrointestinal cancers make up six of them.These include colorectal cancer (9.4%),liver cancer (8.3%),gastric cancer (7.7%),esophageal cancer (5.5%),and pancreatic cancer (4.7%).Multimodal treatment,including chemotherapy,radiotherapy,and surgery,has become a primary option for treating gastrointestinal tumors.Although effective,the use of this treatment is often associated with significant toxic side effects,including diarrhea,nausea,vomiting,and severe malabsorption[3].As the number of chemotherapy cycles increases,tumor cells become less sensitive to chemotherapy drugs,resulting in drug resistance.This can lead to tumor recurrence,ultimately impacting the effectiveness of treatment and the long-term survival of patients[4,5].

In recent years,there has been a growing awareness of the importance of food safety and health,leading more and more people to seek out foods with health benefits and therapeutic effects[6].This concept is known as 'medication-food homology' in traditional Chinese medicine[7].According to this theory,the source of Chinese medicine and food is the same,and some items can only be used to cure diseases (called medicine),others can only be consumed as food (called diet),while most items have both curative effects and can be consumed as food (called medication-food homology).The concept of homologous medicine and food can be traced back to Huangdi Neijing (Yellow Emperor's Internal Classic),which mentioned that food can also be used as medicine (such as a medicinal diet) to improve people's immunity and thereby achieve the effect of preventing or treating diseases.Since the pre-Qin period,people have found that some foods made into soup can not only meet food and clothing needs,but also treat diseases.In the Han dynasty,people began to consciously classify a variety of medicinal materials according to their functions in the Sui dynasty.Some people put forward the idea that all foods have medicinal properties and that diets should pay attention to the concept of mutual promotion and reasonable matching.Bencao Gangmu (Compendium of Materia Medica) of the Ming dynasty detailed the edible methods of medicinal and edible homologous plants,and clarified the appropriate population and usage[8].Nowadays,with the continuous development of medicine and the accumulation of experience,people have found that medicine-food homologous substances have significant advantages in pharmacological activities such as hypoglycemic[9],lipid-lowering[10],antioxidant[11],anti-inflammatory[12],immunomodulatory[13] and anti-tumor activities[14] and have fewer adverse reactions.Related research has gradually attracted attention[15].By 2022,a total of 110 medicinal herbs with medicinal and food homology have been listed by the relevant state departments according to the Food Safety Law of the People's Republic of China and a series of measures such as safety assessment[16].

Ginger is a Zingiber officinale roscoe in the Zingiber family,which was first found in southeast Asia and other tropical areas,and now all countries in the world are planted[17].Ginger was first widely used as a Chinese herbal medicine in China,because it has the effects of relieving cough and asthma,clearing away heat,warming the lung and dispersing cold.It is also consumed as a spice and vegetable,and is a typical medicine-food homologous herb.Ginger is versatile and has remained popular to date.Its extensive pharmacological actions include anti-inflammatory[18],antioxidant[19],hypoglycemic and lipid-lowering[20,21] and significant antitumor activity[22,23].Ginger and its active ingredients possess anti-tumor properties that can effectively combat various gastrointestinal tumors.Figure 1 depicts the types of tumors treated with ginger.

Figure 1 Types of tumors treated with ginger.Ginger has excellent therapeutic effects on liver,pancreatic,stomach,colorectal and laryngeal cancers.

Searching "ginger","cancer","carcinoma","tumor" and "neoplasm" as keywords in PubMed,it was found that there was no review on ginger and its active components in the treatment of gastrointestinal tumors in the past 5 years.More attention is still paid to ginger and its active ingredients in the treatment of single cancers such as breast cancer,colorectal cancer,etc,and the alleviation of nausea and vomiting caused by chemotherapy.We retrieved a review published in 2015 on the treatment of gastrointestinal tumors with ginger,which only focused on theinvitroandinvitroeffects of ginger on gastrointestinal cancer,but it was a long time ago,and the time distance of the cited literature was far away,so the reference value was not great.In this review,the ethnic pharmacology and main active components of ginger were summarized,and the anti-tumor effects of each component of ginger were evaluated to reveal its mechanism of action in the prevention and treatment of gastrointestinal cancers.The specific process is shown in Figure 2.

NETWORK DIAGRAM OF GINGER'S ANTI-GASTROINTESTINAL TUMOR EFFECTS

To investigate the potential anti-gastrointestinal tumor effects of ginger,a network pharmacological analysis was conducted.This analysis took into account the multi-component,multi-target,and multi-level properties of ginger.A total of 22 active ingredients and 156 related proteins were screened from the TCMSP database (https://old.tcmsp-e.com/tcmsp.php) using the criteria of oral bioavailability ≥ 30% and drug-likeness ≥ 0.10 (Supplementary Table 1).The protein name was entered into the multiple proteins section of the STRING database (https://cn.string-db.org),specifically selecting the Homo sapiens species.The gene name corresponding to the protein name was then downloaded and matched (Supplementary Table 2).To construct pological network maps of the 12 active components and 63 corresponding genes,we utilized Cytoscape software 3.9.1.In the figure,the red module represents the herb name,the blue template represents the active ingredient,and the yellow module represents the corresponding gene.The 63 genes were analyzed using the DAVID database (https://david.ncifcrf.gov),and the results were visualized using the bioinformatics online platform (http://www.bioinformatics.com.cn/).The results are shown in Figure 3,and most of the genes were enriched in the tumors.In addition,there are colorectal cancer,gastric cancer,hepatocellular carcinoma,pancreatic cancer and other related gastrointestinal cancer pathways.This provides a theoretical basis for us to study the treatment of gastrointestinal cancer with ginger.

THE MAIN ACTIVE INGREDIENT OF GINGER FOR ANTI-TUMOR EFFECT

Ginger possesses a multifaceted chemical composition that comprises phenolic compounds,terpenes,polysaccharides,fibrils,etc[24].As shown in Figure 4,the phenolic compounds in ginger are mainly gingerol,shogaol,zingerone and paradol.Gingerol can be converted to the corresponding gingerol by heating or storage.After hydrogenation,shogaol can be converted to paradol.Ginger also contains several other phenolic compounds,including zingerone,gingerdione,gingerdiol,6-dehydrogingerol,gingerenone-A,5-acetoxy-6-gingerol,and 6-dehydrogingeradione,etc[25-27].

Figure 4 Structural formulae of the representative components of ginger and the transformation between them.

Gingerol

Gingerol is a general term for a series of congeners with phenolic ketone functional groups and alkyl side chains connecting different numbers of carbon atoms.Gingerol has strong biological activity and pharmacological effects due to its lower solubility in water and chemical instability,and it has anti-inflammatory and anti-tumor effects on a variety of cancers[28].Ginger has therapeutic effects that are believed to be caused by a combination of gingerol derivatives,including 6-gingerol,8-gingerol,and 10-gingerol.These derivatives are responsible for the pungent taste associated with ginger[29,30].

Shogaol

6 -shogaol,one of the main ingredients in ginger,is an alkylphenol compound formed by dehydration of 6-gingerol.Studies have shown that 6-shogaol is the hallmark chemical ingredient of ginger and can be used as a quality control index for ginger.6-shogaol has demonstrated its potential as an effective agent with anticancer,anti-inflammatory,antioxidant,and neuroprotective properties[31,32].The C3-carbonyl group and C5-hydroxyl group (i.e.β-hydroxyl ketone structure) on the hydrocarbon chain of gingerol make the chemical properties of gingerol extremely unstable.Under acidic or heated conditions,shogaol can be formed when the active hydrogen of C4 on gingerol reacts with the hydroxyl group of C5,resulting in dehydration.The conversion of 6-gingerol to 6-shogaol was dependent on p H.6-gingerol was most stable at pH=4,and the reversible conversion was most rapid at 100 ℃ and pH=1[33].Studies have shown that 6-shogaol is superior to 6-gingerol in anti-cancer,antioxidant and anti-inflammatory effects,which may be attributed to the chemical structure of 6-shogaol,which contains α,β-unsaturated carbonyl fragments (Michael receptor)[34-36].

Zingerone

Zingerone is a phenolic alkanone isolated from ginger that is found in up to 9.25% of ginger.Zingerone,a compound with a basic phenolic ring and a methoxy group attached to the benzene ring,has been shown to exhibit significant pharmacological effects such as antioxidant,anti-inflammatory,and anti-cancer activities[37].It has been suggested that zingerone is mainly found in dried ginger,whereas the content of zingerone in fresh ginger is usually very low,but cooking or drying also converts gingerol to zingerone through the reverse aldol reaction[38].

Paradol

According to research,dried ginger contains 6-paradol as its primary active component,which is synthesized through a biotransformation process from 6-shogaol[35].It has a large number of pharmacological effects and has been proven to have anti-tumor and anti-proliferative effects[39,40].

Other ingredients

In addition,the major terpene components in ginger are β-bisabolene,curcumene,α-farnesene,and β-sesquiculene[41].The main components of ginger essential oil are known for their anti-inflammatory and antioxidant effects,as well as their ability to provide neuroprotective and anti-cancer properties[42].

ANTI-TUMOR MECHANISMS OF THE ACTIVE COMPONENTS OF GINGER

Inhibition of tumor cell proliferation

Phorbol 12-myristate 13-acetate (PMA) has been shown to activate transcription factors AP-1 and NF-κB in various cancer cells[43].In colon cancer cells treated with PMA,6-gingerol has been found to down-regulate PMA-induced phosphorylation of ERK1/2 and JNK MAP kinases as well as the activation of AP-1 transcription factor.However,it has little effect on p38 MAP kinase phosphorylation and NF-κB activation.Moreover,6-gingerol has been found to significantly inhibit the proliferation of colon cancer cell SW-480 induced by PMA[44].

Epidermal growth factor receptor (EGFR) belongs to the tyrosine kinase family of ERBB cell surface receptors.Upon binding to its ligands,EGFR undergoes autophosphorylation and activates downstream signaling pathways to promote cell proliferation and metastasis[45].Huetal[46] found that 8-gingerol inhibits the proliferation and migration of colorectal cancer cells by targeting the EGFR/STAT/ERK pathway,and its effect depends on the expression of EGFR.Jiangetal[47] found the anti-pancreatic cancer activity of 6-paradol was observed through its ability to reduce EGFR expression and inhibit phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) signaling activity.

Toll receptor 4 (TLR4) is strongly associated with poor prognosis in cancer patients[48,49].Activation of Wnt/β-catenin signaling contributes to cell proliferation and metastasis in many diseases[50].In addition,TLR4 mediates Wnt/β-catenin signaling in HCC[51].Zhangetal[52] hold that 6-shogaol inhibits the proliferation of HepG2 hepatoma cells by mediating Wnt/β-catenin signaling through TLR4.

Induction of tumor cell cycle arrest

Cyclin D1 is a proto-oncogene that can cause uncontrolled cell proliferation and malignant transformation when overexpressed.Activation of β-catenin signaling induces cyclin D1,which in turn leads to G1/S phase progression and increased proliferation.Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1),a cytokine with pro-apoptotic and antitumor properties,is activated by non-steroidal anti-inflammatory drugs.Leeetal[53] found that the inhibition of cyclin D1 transcription was observed upon treatment with 6-gingerol,which was achieved through the inhibition of βcatenin translocation into the nucleus.Additionally,6-gingerol was found to increase cyclin D1 proteolysisviaproteasomal degradation,leading to growth arrest in colorectal cancer cells.

The p53 gene is responsible for encoding a transcription factor that acts as a tumor suppressor.Its main function is to inhibit cell proliferation by inducing cell cycle arrest and apoptosis[54].The Cip/Kip family of cyclin-dependent kinase inhibitors p21Cip1,p27Kip1,and p57Kip2,initially identified as cell cycle inhibitors mediating growth-inhibitory signals in upstream signaling pathways,has now emerged as a multilayered protein with cell cycle regulatory functions[55].Studies have reported that 6-gingerol induced reactive oxygen species (ROS) generation and p53 activation in LoVo cells,inhibited degradation of p27Kip1 and p21 Cip1,and thus significantly induced cell G2/M phase arrest[56].6-gingerol also induces cell death in p53-expressing mutant cells and destroys them in G1 phase[57].Qietal[58] found that 6-shogaol induced G2/M cell cycle arrest in HCT-116 cells through p53/p21-cdc2/cdc25A crosstalk to achieve tumor effects.

Induced apoptosis of tumor cells

Caspases are a class of cysteine proteases that are activated during apoptosis.Radhakrishnanetal[44] found that 6-gingerol could affect caspase activation and Poly(ADP-ribose) polymerase cleavage to induce apoptosis in colon cancer SW-480 cells using immunoblotting experiments.

Mahlavu cells,which are a subline of human hepatoma cells,are highly refractory to many chemotherapeutic agents and radiotherapy due to their poor differentiation and p53 mutations.Chenetal[59] found that 6-shogaol caused cell death in Mahlavu subline of human liver cancer cells through a process involving oxidative stress and activation of caspases.

Protein kinase C (PKC) is involved in intracellular signal transduction pathways and regulates various functions such as cell cycle,apoptosis and cytoskeleton.Leeetal[53] confirmed that 6-gingerol stimulates colorectal cancer cell apoptosis by upregulating NAG-1 and through the PKCε pathway.

Cathepsin D plays a crucial role in the process of apoptosis.Decreased activity of cathepsin D leads to inhibition of cytochrome c release.Mansinghetal[60] found that treatment of human gastric cancer AGS cells with 6-gingerol results in a decrease in mitochondrial membrane potential.This decrease leads to the up-regulation of cytochrome c,which in turn triggers the caspase cascade and induces cell apoptosis.Yangetal[61] conducted a study which suggests that cathepsin D may play an active role in mediating apoptosis induced by 6-gingerol in HepG2 cells.In another study,the anticancer activity of 6-shogaol in laryngeal cancer (Hep-2) cells was investigated.The study revealed that 6-shogaol induces apoptosis in Hep-2 cells through oxidative damage and the regulation of apoptotic markers[62].Additionally,6-shogaol has been found to induce apoptosis in COLO 205 cells through ROS production,caspase activation,and GADD 153 expression[63].

Abdel-Rasoletal[64] found that ginger extract induced the expression of apoptosis-related genes,thereby inducing apoptosis.This may be the mechanism of ginger extract's anti-HCT-116 colorectal cancer (CRC) cells and dimethylhydrazine (DMH)-induced colorectal tumor activity.In HCT116 colon cancer cells treated with zingerone,there was a significant increase in the production of reactive oxygen species,while the mitochondrial membrane potential and antioxidant levels in the cells were decreased.These results indicate that zingerone can induce oxidative stress-mediated apoptosis to achieve the purpose of anti-colon cancer[65].

MAPK is a crucial signal transmitter from the cell surface to the nucleus.It is composed of four subfamilies,namely ERK,p38,JNK,and ERK5,and plays a vital role in regulating various physiological processes such as cell growth,differentiation,and apoptosis[66].In human colon cancer,HCT116 cells,both 10-gingerol and 6-shogaol induce apoptosis through the mitochondrial pathway.Specifically,10-gingerol activates the MAPK pathway while 6-shogaol's induction is regulated by the bcl-2 family[58,67].

The endoplasmic reticulum (ER) plays a crucial role in regulating protein synthesis,folding and intracellular calcium levels.However,the loss of these functions can lead to ER stress,which is associated with apoptosis.Huetal[68] conducted a study that found 6-shogaol to induce apoptosis in human hepatoma SMMC-6 and SMMC-7721 cells through ER stress-related mechanisms.

Inhibition of tumor invasion and metastasis

Tumor cells exhibit malignant behaviors through invasion and migration.Invasion is characterized by the occupation of adjacent host tissues by malignant tumors from primary or secondary tumors.On the other hand,metastasis is the recurrent multistep process of the primary tumor spreading to distant organs[69].Tumor metastasis is a significant cause of cancer treatment failure and recurrence[70].

Angiogenesis is a crucial factor in tumor progression and is caused by an imbalance between pro-angiogenic and antiangiogenic factors.This imbalance is mainly due to the excessive production of vascular endothelial growth factor (VEGF) triggered by tissue hypoxia[71].Farombietal[72] conducted a study on mice with colon cancer and found that 6-gingerol had an inhibitory effect on angiogenesis by reducing the concentrations of VEGF,angiopoietin-1,fibroblast growth factor and GDF-15.

Epithelial-mesenchymal transition (EMT) is a significant biological process that allows malignant tumor cells derived from epithelial tissue to gain the ability to migrate and invade surrounding tissues.Transforming growth factor beta (TGF-β) is a master regulator of EMT,which can regulate a variety of cellular functions.Kimetal[73] found that zingerone and its derivatives inhibited TGF-β1-induced EMT,thereby inhibiting the migration and invasion of SNU182 hepatoma cells.

Matrix metalloproteinases (MMPs) are crucial molecules in the regulation of tumor invasion,metastasis,proliferation,differentiation,and cell death.They are responsible for the degradation of most extracellular matrix and basement membrane protein components[74].Tissue inhibitors of metalloproteinases (TIMP) is a natural inhibitor of MMPs by inhibiting their proteolytic activity.An imbalance between MMPs and related TIMPs may play a vital role in the aggressive phenotype of malignancies[75,76].Wengetal[77] found that 6-shogaol and 6-gingerol may exert anti-invasion effects on hepatocellular carcinoma cells by regulating MMP-9 and TIMP-1.

Tight junctions (TJs) are complexes that help cells adhere to each other and are crucial for maintaining the integrity of epithelial and endothelial barriers[78].These complexes are important in the gut and liver for barrier formation,but can also contribute to the development of colorectal and gastric cancers[79].The transcription factor NF-κB plays a crucial role in the signaling pathways of metastasis and invasion[80].The transcription factor NF-κB is involved in signaling pathways related to metastasis and invasion.6-gingerol was found to inhibit the nuclear translocation of Snail,which is regulated by NF-κB[81].Kim and Kim[81] put forth a novel approach to prevent cancer invasion and metastasis.They proposed using 6-gingerol to restore TJS in PANC-1 cells.The results of their experiment demonstrated that 6-gingerol can regulate TJ-related proteins and effectively inhibit the invasion and metastasis of PANC-1 cells by inhibiting the ERK pathway and NF-κB/snail pathway.

Metadherin (MTDH) is a specific tumor-associated antigen that plays a significant role in promoting cancer proliferation,invasion,stance,chemoresistance and angiogenesis[82].Fangetal[83] found that zingerone inhibited the invasion and migration of HCC cells by inhibiting the MTDH-mediated PI3K/Akt pathway.

Anti-inflammatory and anti-oxidative

Inflammation is a natural response of the body to tissue damage caused by various factors such as physical injury,ischemic injury,infection,exposure to toxins,or trauma.This response triggers changes in cells and the immune system,which promote the repair of damaged tissue and cell growth at the site of injury.However,this environment can also be conducive to the development and progression of cancer[84].Therefore,targeting inflammation is considered an effective strategy for both cancer prevention and treatment.

It is a widely accepted fact that tumor cells often exhibit excessive expression of proinflammatory mediators,which include proteases,cytokines and chemokines.Among these,cytokines such as tumor necrosis factor α (TNF-α),NF-κB,and interleukin-10 have been linked to human cancer and can either facilitate or impede tumor growth[85].Studies have shown that ginger extract can significantly reduce the expression of NF-κB and TNF-α to play a role in anti-cancer and anti-inflammatory effects in liver cancer rats[86].Ginger extract can also exert anti-inflammatory activity by inhibiting pro-inflammatory markers,alleviating oxidative stress and inflammatory response associated with gastric cancer[87].Ajeigbeetal[88] discovered that 6-gingerol exhibited protective properties against the development of colorectal cancer in mice induced by azoxymethane/dextran sodium sulfate.The researchers attributed this mechanism to the anti-inflammatory and antioxidant properties of 6-gingerol.

Nuclear factor E2-related factor (Nrf-2) can respond to the generation of ROS and regulate the NF-κB transcription factor,ultimately playing a crucial anti-inflammatory role in cell protection[89,90].Ganaieetal[91] found that zingerone showed promising chemopreventive potential in DMH-induced colon carcinogenesis by inhibiting reactive oxygen species and modulating Nrf-2 and NFκB-mediated inflammation.

Induction of autophagy in tumor cells

Autophagy is a cellular process that involves the use of lysosomes to break down cytoplasmic proteins and damaged organelles.This process is regulated by autophagy-related genes[92].Autophagy is a therapeutic target in cancer because of its potential ability to regulate cell death[93].6-Shogaol has been shown to induce the production of ROS and ER stressrelated proteins,and subsequently activate autophagy in human hepatocellular carcinoma HepG2 cells[94].Moreover,8-parador induces mitochondrial damage,thereby inducing PTEN-induced kinase 1/Parkinson-mediated mitophagy,thereby inhibiting gastric cancer progression[95].

REDUCE THE ADVERSE REACTIONS OF CHEMPRADIOTHERAPY AND IMPROVE THE EFFICACY

Chemotherapy induced nausea and vomiting (CINV)

CINV is a common side effect of antineoplastic chemotherapy and can significantly impact the quality of life and physical function of patients during treatment[96].Ginger,which has been used as an antiemetic in various traditional medical systems for over 2000 years,has shown promise in reducing the severity of CINV[97].

CINV can occur through relatively independent peripheral and central systems,and many neurotransmitters are involved in its pathogenesis.Some studies have shown that gingerol can significantly inhibit CINV,and its mechanism of action may be related to the inhibition of central or peripheral increases in 5-HT,substance P,and DA[98,99].Similarly,gingerol has the ability to inhibit the increase in central or peripheral dopamine by inhibiting D2R and TH,while also accelerating dopamine transporter scan.This mechanism of action has been shown to effectively inhibit CINV in rats[100].Tianetal[101] used two models of emesis to evaluate the antiemetic effects of gingerol.The study revealed that administering gingerol reduced the instances of kaolin consumption in rats induced by cisplatin and vomiting episodes in minks.The reduction in these instances may be attributed to the simultaneous regulation of the 5-HT,SP,and DA systems.According to Fengetal[102],6-gingerol has been found to be just as effective as ondansetron in treating cisplatin-induced pica in rats.Some researchers have suggested that the potential impact of 6-gingerol on CINV may be attributed to its ability to regulate the TPH/MAO-A/SERT/5-HT/5-HT3 receptor system,leading to a reduction in 5-HT levels[103].An alternative hypothesis is that 6-gingerol significantly reduced intracellular Ca2+levels and inhibited 5-HT3Rs-mediated Ca2+/CaMKII/ERK1/2 signaling pathway in NG108-15 cells,resulting in an antiemetic effect on CINV[104].

Cardiotoxicity

Solimanetal[105] suggested that pretreatment with zingerone significantly reduced the cardiac histological abnormalities and cardiotoxicity indicators elevation induced by cisplatin or gamma radiation.In addition,zingerone attenuated the elevation of inflammatory markers,including TNF-α levels,myocardial peroxidase activity,and cyclooxygenase-2 protein expression.These results reveal the potential of zingerone as a therapeutic intervention for chemotherapy-and radiotherapy-induced cardiac injury.Research shows that ginger can improve cisplatin-induced myocardial fiber organization disorder,destruction and degeneration,down-regulation of P53,TNF-α immune expression,serum creatinekinase and actate dehydrogenase levels.The results showed that ginger had a protective effect against cisplatin-induced cardiotoxicity mainly through its anti-apoptotic,antioxidant and anti-inflammatory effects[106].

Adriamycin,a commonly used anti-tumor medication,is often limited in clinical use due to its potential for causing cardiac toxicity.It has been concluded that ginger extract can reduce the cardiotoxicity of Adriamycin in mice hepatocellular carcinoma by oxidative stress,increase of VEGF and downregulation of MDR1[107].In addition,6-gingerol can ameliorate doxorubicin-induced cardiotoxicity through the effects of NF-κB and protein glycosylation[108].Gingerol was also shown to prevent DOX-induced vascular injury[109].

Liver and kidney injury

Diethylnitrosamine (DEN) is a known carcinogen that can cause severe liver damage and liver cancer when orally administered[110].Recent research by Alsahlietal[111] suggests that DEN induces oxidative stress in the liver and changes in hepatocytes.However,they found that 6-gingerol has a significant hepatoprotective effect on DEN-induced liver injury in rats by reducing oxidative stress and inflammation.Similarly,Mansouretal[112] demonstrated that ginger extract was also protective against early oxidative stress and inflammation in rat liver induced by the carcinogen DEN.

Nephrotoxicity is also a major side effect of cisplatin therapy,which limits the application and efficacy of cisplatin in cancer treatment[113].The administration of 6-gingerol subsequent to cisplatin treatment resulted in the improvement of renal insufficiency and tubular injury.This was observed through reductions in serum creatinine and blood urea nitrogen levels,as well as improvements in histological abnormalities[114].The study's findings indicate that 6-gingerol has therapeutic properties that can mitigate the effects of cisplatin-induced acute kidney injury.This is achieved through its ability to curb oxidative stress,renal tubular cell death,and inflammation.Zingerone can not only significantly reduce the level of malondialdehyde in tissue after cisplatin administration,but also significantly preserve the activities of catalase and glutathione peroxidase in renal tissue,and inhibit cisplatin-induced inflammation by reducing the level of TNF-α,thus playing a renoprotective effect[115].Radiotherapy is an effective cancer treatment; however,its use is often limited due to the acute and chronic side effects it has on normal organs.Saberietal[116] conducted a study which found that radiation causes kidney damage through peroxidative DNA damage and inflammation.The study also showed that pretreatment with ginger antioxidants,acting as an oxidant and anti-inflammatory agent,can alleviate these effects.

Neuropathic pain

Oxaliplatin is a platinum-based anticancer drug that is widely used in the treatment and adjuvant chemotherapy of metastatic and advanced colorectal cancer.The induction of peripheral neuropathic pain shortly after oxaliplatin injection can be a severe issue,potentially leading to treatment interruption and significantly impacting the treatment of cancer patients[117].Kimetal[118] discovered that the use of 6-shogaol was effective in reducing oxaliplatin-induced neuropathic pain in mice.This was achieved through the activation of serotonergic receptors and gamma-aminobutyric acid in the spinal cord.Ginger extract also significantly alleviated allodynia induced by oxaliplatin treatment alone,possibly by increasing the expression of 5-HT1A receptor mRNA in the spinal cord[119].

Damage to other organs

Leeetal[120] found that zingerone attenuated cisplatin-induced ototoxicity through mechanisms including oxidative stress,inflammation,and apoptosis.Radiotherapy for pelvic and abdominal tumors can lead to intestinal injury,which is a common acute complication.However,zingerone derivatives have demonstrated potential for protecting against radiation-induced intestinal damage by promoting the proliferation and differentiation of intestinal crypt stem cells.These derivatives have been shown to inhibit apoptosis and reduce DNA damage,which contributes to their protective effects[121].

The off-target testicular toxicity of anticancer drug cisplatin is a concern in the clinic.Studies have shown that fresh ginger juice can reduce cisplatin-induced testicular toxicity in rats by preventing oxidative stress,endocrine imbalance and NO/iNOS/NF-κB signaling[122].

COMBINATION THERAPY

Aspirin is used clinically to reduce pain and inflammation.There is mounting evidence that daily low-dose aspirin can reduce the incidence of colorectal cancer[123].However,the primary drawback of aspirin usage is its potential to cause gastrointestinal ulcers and bleeding as side effects.Zhuetal[124] synthesized aspirin and 6-gingerol and found that they could exert enhanced anticancer properties in vitro without deleterious effects on the gastric mucosa.Therefore,the combination of aspirin and 6-gingerol can reduce the cardiovascular risk and the occurrence of gastrointestinal complications associated with aspirin,which may be an effective alternative method.

It is well known that the combination of traditional Chinese medicine and ginger,which are homologous to traditional medicine and food,plays a crucial role in diet and medical treatment.In the ancient Chinese books Huangdi Neijing and Jingui Yaolue,jujube and ginger are the most common drug pairs in the compatibility of traditional Chinese medicine.Wuetal[125] extracted and purified the major polysaccharide fraction of jujube as a potential anticancer compound,and further investigated the antitumor activity of the combination of jujube polysaccharide and 6-gingerol.The results showed that the combination of jujube polysaccharide and 6-gingerol had a high inhibitory effect on the proliferation of SW620 cells through apoptosis pathway and G0/G1 phase arrest mechanism.Ganoderma lucidum is also one of the most famous traditional Chinese herbs and has been used for 1000s of years.It has been found that the combination of ginger and Ganoderma lucidum extracts exhibits synergistic anti-proliferative and apoptotic effects on colorectal cancer cells[126].Saeedifaretal[127] evaluated the anticancer activities of ginger and licorice extracts and the synergistic effects of their combinations.The results showed that their combination synergistically inhibited colon cancer cell growth and increased apoptosis.Therefore,the combination of traditional Chinese medicine and ginger can be developed into an effective anti-tumor agent for functional food and public health in the pharmaceutical industry,which is worthy of further exploration.

The combination of anti-cancer agents from natural products and ginger can help people better fight cancer and reduce adverse reactions.Prescottetal[128] investigated the potential of the combination of the natural derivative sanguinarine as a novel anticancer agent and ginger extract as an ultrasound sensitizer for sonodynamic therapy in pancreatic cancer PANC-1 cells in vitro.The results showed that all their combinations were cytotoxic in a dose-dependent manner in the presence of PANC-1 cells.Besides,higenamine,the active component of aconitum,combined with 6-gingerol has cardioprotective effect on Adriamycin-induced cardiotoxicity by activating the PI3K/Akt signaling pathway[129].

Chemotherapy resistance in colorectal cancer is a major challenge in cancer treatment.Recent studies have shown that using a combination of clinical drugs and ginger derivatives could potentially improve the development of resistance.By combining 5-fluorouracil (5-FU) and 6-shogaol,AMPK signaling is activated,leading to the restoration of the effect of SREBP-1 upregulation.This,in turn,reduces the sensitivity of CRC cells to 5-FU cytotoxicity[130].The study conducted by Leeetal[131] and team showed that the combination of ginger extract and oxaliplatin has the potential to induce cytotoxic effects in oxaliplatin-resistant CRC cells.This effect is achieved through modulation of CXCR4 expression,indicating a synergistic effect between the two compounds.Their combination seems to provide a therapeutic strategy for the treatment of chemoresistance in CRC.Studies on gingerol and γ-tocotrienol have shown that their combination treatment can inactivate cell cycle process by interfering with cell cycle,down-regulating Wnt signaling pathway,caspase-independent programmed cell death caused by mitochondrial dysfunction,activating endoplasmic reticulum unfolded protein response,disrupting DNA repair mechanism,down-regulating FOXM1 and other major proliferation genes[132,133].Thus,enhancing the effect of chemotherapy.These studies have promoted the clinical application of ginger in the treatment of CRC.

According to research,Gelam honey from Malaysia possesses anti-cancer properties.It has been found to inhibit cell proliferation and DNA damage,induce apoptosis,and cause cell cycle arrest in a range of cancers.Weeetal[134] proposed that the combination of Gelam honey and ginger had a dose-dependent effect on inducing apoptosis in colon cancer HT29 cells.The highest rate of apoptosis was observed with the combined treatment.Hakimetal[135] also studied that the combination of these two natural compounds had a synergistic effect in the inhibitory effect on HCT 116 CRC cells and could enhance the anticancer effect of 5-FU on HCT 116 CRC cells.

NEW DRUG DELIVERY SYSTEMS

The extraction of active components from ginger holds promises for the development of modern drugs to treat gastrointestinal tumors.However,the properties of these components,including stability,solubility,irritation,and bioavailability,present challenges.To overcome these issues and expand the clinical use of ginger,innovative drug delivery technologies can be employed to address the problems faced in the drug delivery system.

The structure of liposomes is very similar to that of cell membrane,which makes it highly biocompatible and biodegradable.Therefore,liposomes can protect the drug from enzymatic degradation before reaching the lesion site.At the same time,the drug can be hidden inside the liposomes in the form of physical encapsulation,which can improve the stability of the drug,reduce the toxicity of the drug,increase the dose of the drug,and have a better therapeutic effect[136,137].Yavarietal[138] prepared nanoliposomes containing ginger extract and investigated their effects on colorectal cancer cells.This finding further emphasizes that liposomes containing ginger extract enhanced anticancer properties by increasing the induction of apoptosis and stimulating the immune system.

The use of deep eutectic solvents (DES) as a green solvent for extracting bioactive compounds from plant materials has gained popularity due to its numerous benefits such as biodegradability,sustainability,low toxicity,and affordability[139].Recent studies have demonstrated that fermented DES-ginger extract can enhance the cytotoxicity and therapeutic effects of oxaliplatin in drug-resistant CRC cells by inhibiting NF-κB and CXCR4[131].

Chitosan is a biodegradable polymer.Due to its good biodegradability,strong adhesion to biological mucosa,nontoxicity and histocompatibility,it is an ideal drug carrier[140,141].Nano-microspheres prepared by chitosan can improve the stability of drugs,improve the solubility of hydrophobic drugs,change the route of administration,increase the absorption of drugs,improve the bioavailability of drugs,reduce the adverse reactions of drugs,and can also be sustained release,controlled release,or targeted release of drugs[142].Therefore,chitosan nanospheres have great application potential as drug carriers.Abo Mansouretal[107] found that loading ginger extract into chitosan nanoparticles enhanced cytotoxicity and reduced cardiotoxicity of doxorubicin in murine hepatocellular carcinoma.

The field of biomedicine has seen considerable progress with the application of nanotechnology,which has provided a new solution to overcome the challenges associated with cancer treatment.In recent times,there has been a growing focus on the synthesis of nano-ZnO materials and their potential for anti-tumor activity[143,144].In a study by Ahamedet al[145],ZrO2-doped ZnO/reduced graphene oxide nanocomposites were synthesized using ginger rhizome extract.The ginger extract facilitated a synergistic effect between ZnO,ZrO2,and rGO,resulting in high anticancer efficacy and improved biocompatibility.

CONCLUSION

Cancer is a disease that occurs when the body cells lose their normal regulation and start to excessively proliferate,which poses a threat to human health.Ginger has been found to have significant advantages in the treatment of gastrointestinal tumors due to its wide range of pharmacological activities and various application routes.

This article reviews the application of ginger and its active components in the treatment of gastrointestinal tumors,focusing on the anti-tumor mechanism of ginger,the reduction of adverse reactions of radiotherapy and chemotherapy,the combination of ginger and modern medicine,and new drug delivery technologies,so as to inhibit the occurrence and malignant progression of tumors.Ginger's active ingredients have the ability to regulate several signaling pathways such as PI3K/Akt/mTOR,Wnt/β-catenin,EGFR,and NF-κB.This regulation is achieved through components such as 6-gingerol,6-shogaol,zingerone,and others that can directly or indirectly act on signal targets,leading to an anti-tumor effect.

Strength and limitations

As a traditional Chinese herbal medicine with a long history of medicinal use,ginger's active ingredients and pharmacological effects are gradually being recognized and explored through available scientific research.Numerous studies have shown that its natural active ingredients have significant effects in the treatment of many diseases such as cancer and inflammation,with fewer side effects,which is of great significance in anti-cancer research.In addition,ginger is a common material,and people are paying more and more attention to health care,so the utilization of ginger's medicinal and food values will have a broad prospect.

Several experimental studies have confirmed the anti-tumor properties of ginger.However,further research is necessary to address the current deficiencies and limitations in order to fully understand and utilize its potential in cancer treatment.Furthermore,the majority of current research findings are derived from in vitro cell experiments,with fewer in vivo animal experiments and clinical trials.Therefore,it is imperative to emphasize the integration of basic experiments and clinical trials.Recent years have seen successful developments in drug delivery systems,which have tackled issues such as stability,solubility,and bioavailability.However,research on new delivery technologies for other active components of ginger remains scarce.Despite the growing recognition of the benefits of ginger combined with modern medicine,significant challenges and barriers to its widespread use persist.

Perspectives on future research

Ginger contains several antitumor compounds that can improve the effectiveness of anticancer drugs and minimize the negative side effects of radiation and chemotherapy.As a result,it has the potential to be a valuable addition to cancer treatment regimens.To further investigate and develop the anti-tumor properties of ginger,it is suggested to use molecular biology techniques to explore its anti-tumor mechanism and confirm it through in vivo experiments.Additionally,comparing the anti-tumor activities of different components of ginger and investigating the optimal compatibility and advanced drug delivery system can provide further insight into the anti-tumor effect of ginger.With the potential for more active ingredients to emerge from ginger in the future,it could offer safe and effective natural drugs and preparations for treating various tumors in clinical settings.

ACKNOWLEDGEMENTS

The authors would like to acknowledge Joanna Tibenda for revising the article.

FOOTNOTES

Author contributions: Chen GQ wrote the paper; Chen GQ and Nan Y drew the figures; Huang SC,Ning N,Du YH,Lu DD,Yang YT,and Meng FD collected the data; Yuan L made critical revisions of this paper; All authors contributed to the original ideas and writing of this paper.

Supported by"Young Scholars of Western China"(Class A)_West Light Foundation of the Chinese Academy of Sciences,No.XAB2019AW13; Ningxia Natural Science Foundation,No.2022AAC02039.

Conflict-of-interest statement: The authors declare having no conflict of interests for this article.

Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is non-commercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin: China

ORCID number: Yi Nan 0000-0002-5511-9266; Shi-Cong Huang 0009-0002-5996-0797; Yu-Hua Du 0000-0002-9669-8065; Ling Yuan 0000-0003-2838-0976.

S-Editor: Qu XL

L-Editor: Filipodia

P-Editor: Zhang XD