Cancer is still a difficult problem in the medical community and a huge threat to human health. According to the statistics of the World Health Organization, the incidence of cancer is increasing year by year. It is expected that2025In, the world will produce2 000Million new cancer cases^[1]Therefore, it is urgent to find effective prevention and treatment methods for malignant tumors. However, the current conventional means such as surgery, chemical drugs and radiotherapy have limited efficacy, and sometimes lead to serious side effects and drug resistance^[2]。

Natural anticancer products have attracted much attention because of their low side effects and wide distribution. Many studies^[3-6]It is confirmed that the polyphenols of green tea have the efficacy of preventing and controlling cancer. Catechins are the main polyphenols in green tea, which have a variety of biological activities, includingEpigallocatechin gallate（epigallocatechin-3-gallate，EGCG）About% of the total catechins in green tea50%～80%, and the highest biological activity^[7]。EGCGIt belongs to flavanols, and its molecular structure contains3Aromatic rings（A、B、D），3By1Pyran rings（C）Connected together.EGCGThis structure makes it have strongOxidation resistance，This antioxidant activity is derived fromBand/orDHydrogen atom or one electron transfer of hydroxyl groups on rings^[8]。EGCGyes1Amphoteric molecules, which are both hydrophilic and lipophilic^[9]This feature not only allows it to be fully dissolved and widely distributed in the body fluid environment, but also allows it to cross the cell membrane and combine with intracellular targets.EGCGThis unique structural feature endows it with anticancer properties, making it not only play a role in preventing cancer at the initial stage of carcinogenesis, but also have important significance in controlling the progression and metastasis of cancer,EGCGCan act on a variety of cancer types such as liver cancer^[10], lung cancer^[11]And prostate cancer^[12]Et al.

In this paper, we reviewed the antioxidant, pro oxidant, cancer cell cycle arrest, tumor cell angiogenesis inhibition, cancer apoptosis induction and regulationmicro RNAIn recent years, domestic and foreignEGCGResearch status of anticancer molecular mechanism. It should be emphasized that this paper summarizes the impactEGCGFactors for the transformation of antioxidant and pro oxidant effects. EGCGIt has both antioxidant and pro oxidant effects, and under different physiological environments, this2The emphasis of these functions is different, so they can play different functions in different stages of carcinogenesis: in the stage of preventing carcinogenesis, it plays a leading role in increasing the endogenous antioxidant capacity of the body and then scavenging reactive oxygen species; In the control of cancer development stage, the role of promoting oxidation and killing cancer cells is more important. In addition, in order to solveEGCGThe problem of low bioavailability. This article outlines the current methods to improve this problem3Strategies: nano packaging technologyEGCGThe synergistic combination and molecular modification techniques (e.gAcetylated EGCGEtc,Our company can provide EGCG acetylation, methylation, glycosidic modification and other services. Welcome to consult）. The purpose of this paper is toEGCGThe research progress of anticancer molecular mechanism and its application improvement strategies are reviewed and prospected, in order to further exploreEGCGThe anticancer mechanism and its application, as well as the development direction of the development and utilization of cancer therapeutics or adjuvant therapeutics, provide references.

1  EGCGMolecular mechanism of anticancer

1.1  Regulation of oxidative stress

Free radicals are a very active group in the human body, including hydrogen peroxide（H₂O₂）, superoxide anion radical and hydroxyl radical（•OH）Et al., if the production and scavenging of free radicals lose balance, ROS（ROS）The series of compounds will exist for a long time, and then cause the oxidative stress reaction of cells.ROSAffect the activity of some proteins and enzymes in the body and causeDNAOxidative damage occurs,ROSCan also activate nuclear transcription factors-κB（NF-κB），NF-κBRegulates the expression of cancer-related cytokines and related enzymes, such as tumor necrosis factor-α（TNF-α）, cyclooxygenase（COX）And matrix metalloproteinases（MMPs）Et al., which eventually triggered cell carcinogenesis^[13]。

EGCGIs a commonly used antioxidant that reducesROSIt plays an important role in cancer prevention and control. At present, there are many research findingsEGCGPresence of Pro oxidant effects^[14-16], indicating thatEGCGIt not only has strong antioxidant effect, but also shows Pro oxidative properties in some cases.

1.1.1  antioxidant EGCGIts structure contains multiple ortho - or meta phenolic hydroxyl groups, which are the main active functional groups for its antioxidant and free radical scavenging activities^[17]。EGCGalleviateROSThe ways of stress include:（1）Directly remove excessiveROS^[18]；（2）Improve the antioxidant enzyme activity, so that the related enzymes can be cleared more efficientlyROS；（3）Chelate metal ions; The（4）Regulation of cellular signaling pathways. The basic mechanism of antioxidant function is to inhibit the expression of redox sensitive transcription factors, such asNF-κB, nuclear activator protein1（AP-1）Et al^[19]. Gao Wenbo et al^[20]findEGCGBy inhibiting the activity of prooxidant enzymes and upregulating antioxidant enzymes [Such as glutathione peroxidase（GSH-Px）, superoxide dismutase（SOD）Et al] The activity of the antioxidant reaches the purpose of antioxidation.EGCGCan chelateZn²⁺、Cu ²⁺、Fe³⁺And other metal ions to form inactive compounds, preventing metal ions from oxidizing and avoiding the generation of free radicals^[21]。EGCGCan activate nuclear transcription factors in ratsE2Correlation factor2（Nrf2）/KelchkindECHRelated proteins1（Keap1）Pathway, which in turn eliminates fluoride induced oxidative lung injury^[22]。

1.1.2  Pro oxidant EGCGAs an antioxidant, it can also undergo oxidation.EGCGThe autoxidation mechanism is based onEGCGQuinoneEGCGFormation of related compounds such as dimeric Quinones^[23]。EGCGUnstable,BRing andDRings can be oxidized,EGCGThe main oxidation sites during autoxidation areBRing,EGCGThe autoxidation of further leads toROSFormation of^[24]Studies have found that no matter whether there are cells in the culture medium,EGCGCan be produced by automatic oxidationH₂O₂, addSOD（CAT）SuppressableEGCGAutoxidation and dimerization of^[25]。

EGCGPro oxidation can produceROS, causing cellular oxidative stress, which plays an important role in damaging and killing cancer cells.EGCGGeneratedROSAt leastH₂O₂And superoxide anion radicals2Free radicals^[26]。EGCGproduceROSMethod: produced by pyrogallol moietyH₂O₂; activate Fenton（Fenton）Reaction^[27]; rightCa²⁺/Calmodulin dependent protein kinase（CaM kinase）Role of^[28]。EGCGThe high concentration ofROSIt can induce tumor apoptosis and help to reduce the tumor size, and the low concentration produced by its pro oxidant effectROSProtect the body from carcinogenesis by inducing endogenous antioxidant system^[29]。ROSAs an upstream molecule, it can trigger the signaling pathway, such asROS/Adenylate activated protein kinase（AMPK）The regulation of signaling isEGCGOne of the mechanisms of anti-tumor^[30]。N-（NAC）It has free radical scavenging activity and is reported to protectH₂O₂Induced cytotoxicity, but not protectionEGCGInduced cell death^[27],EGCGInduced tumor cytotoxicity also includes tumor specific mechanisms that induce mitochondrial damage.

1.1.3  Antioxidant and pro oxidant  EGCGIt has antioxidant and pro oxidant effects, which2The nature of these actions is diametrically opposite,EGCGThe actual role depends on the cell type, concentration, and environmentalpHvalue^[31]。

Numerous studies have shown that cell type influencesEGCGPlay a role, usuallyEGCGIt plays an antioxidant role in normal cell tissues, while it exhibits Pro oxidative properties in tumor cells, i.eEGCGIt has differential effects on different cells, such asEGCGIt has antioxidant effects in normal cells, but induces oxidative stress in oral cancer cells^[15]；EGCGReduced the toxicity of chemotherapy to normal cells, but led to the toxicity to cancer cells^[14]；EGCGIn normal colonic epithelial cellsNCM460It plays an antioxidant role in colon cancer cells, while it exhibits Pro oxidative properties in colon cancer cells^[32]. whileEGCG. It was found that compared with normal cells, theROSIncreased levels^[33]. however, high levels ofROSIt can also cause damage to cancer cells, so they may rely on a powerful endogenous antioxidant system that can alleviate oxidative stress and thus promote cancer cell proliferation^[34],EGCG.

EGCGIt mainly plays an antioxidant role at low concentration and a pro oxidant role at high concentration.EGCGIt has differential effects on different cells, and low concentrations ofEGCGIt can play an antioxidant role to inhibit oxidative stress and protect normal tissue cells from carcinogenic damage^[16]. studies have shown that rats ingested0.1% EGCGCan reduce oxidative stress, in0.2%or0.5%EGCGIt has no such effect, indicating thatEGCGIts effective concentration is one of the determinants of its pro oxidant or antioxidant activity^[35]Several studies have shown that high concentrations ofEGCGCan play a pro oxidant role to induceROSIncreased levels, eventually leading to tumor apoptosis^[36-38]Another study found that^[39]，EGCGThe milder biological concentration is1～10 μmol/L, of this concentration rangeEGCGCan produce low levels ofROS, which in turn stimulates a variety of signal transduction pathways and triggers the protective mechanism of normal cells. In addition,EGCGEnvironmentalpHValue is also a factor affecting its role, such asEGCGstaypH 7While it exerts antioxidant effect under acidic conditions^[40]。

EGCG.

1.2  Arrest of tumor cell cycle

The cell cycle is the whole process of continuously dividing cells from the end of the last mitosis to the completion of the next mitosis, includingDNAPre synthetic stage（firstgap，G₁Period)DNASynthetic phase（synthesis，SPeriod)DNAAnaphase of synthesis（second gap，G₂Phase) and cell division phase（mitosis，MPeriod). Like normal cells, tumor cells have a certain cell cycle, while the cycle regulation mechanism of tumor cells is disordered, causing unlimited cell proliferation. Therefore, inducing tumor cell cycle arrest is expected to become an effective way of tumor prevention and treatment.

In the normal process of cell physiology, the regulation of cell cycle involves cyclins（Cyclin）And cyclin dependent kinase（CDKs）Complex formed by bindingCyclin D/CDK4、6andCyclin E/CDK2, they jointly drive the cell cycle. ,Cyclin DDependencyCDKRetinoblastoma protein（retinoblastomaprotein，Rb）Phosphorylation, breaking its association with transcription factorsE2FThe combination ofE2FCan induce the expression of related genes regulating the cell cycle^[41]. in general, in tumor cellsCyclinandCDKsWill be overexpressed^[42]。KruppelLike factor4（KLF4）It's a mammalKLFOne of the family members is aDNACombined with transcription factors, it can regulate a variety of cellular processes, including proliferation, differentiation, apoptosis and motility^[43]. research findingsKLF4Can be down regulated byCyclin D1And upregulationp21And showed the function of treating cancer^[44]. found in a variety of cancer tissuesKLF4The tumor suppressive effect of, such as gastric cancer^[45], prostate cancer^[46], lung cancer^[47]And bladder cancer^[48]Et al. stayKLF4In the study of tumor suppressive effect, it is only found in gastric cancer cells at presentEGCGCan be regulated by mediatingKLF4To play a tumor suppressive role, which willEGCGTreatment of gastric cancer cell linesNCI-N87, found thatEGCGUpregulated in a dose-dependent mannerKLF4, thereby increasing the expression ofp21And reduceCDK4andCyclin D1The expression of Bcl-2 can arrest cancer cells inG₀/G₁stage^[45]. in addition, zhangchunxia et al^[49]The study found that,EGCGTheHT29Cell arrest atSPhase, hindering its directionG₂Phase transformation, thus playing the role of anti colon cancer cells. Zhang Yong et al^[50]The study found that,EGCGBy affecting the expression of related inflammatory signaling molecules, such as upregulationTNF-αProtein, down-regulation of heme oxygenase（HO-1）-10（IL-10）Levels, thereby arresting cells atG₂/MPhase, eventually leading to hepatoma apoptosis. Therefore, in the cancer cell cycle4Stages,EGCGCan exert a blocking effect toG₀/G₁The block effect of phase I was the most obvious.

1.3  Inhibit tumor angiogenesis

One of the reasons why tumors are difficult to treat is tumor metastasis, which is the basic feature of malignant tumors. Angiogenesis is a process of forming a new vascular network from existing blood vessels, which provides nutrients, oxygen and metabolic waste for cancer cells, and plays an important role in tumor occurrence, invasion and metastasis^[51]. research shows that^[52-53], benign tumors have sparse and slow angiogenesis; While the angiogenesis of malignant tumors is dense and rapid. Therefore, inhibiting tumor angiogenesis is one of the important strategies to treat tumors.

During angiogenesis, vascular endothelial growth factor（VEGF）Play a key role,VEGFIt can promote the mitosis of vascular endothelial cells and has a strong effect on stimulating the formation of blood vessels^[54]. thereforeVEGF,EGCGrightVEGFShowed a significant effect: inhibitionVEGF, including inhibition of extracellular signal regulated kinases-1（ERK-1）AndERK-2Activating and repressing transcription activating factors（State 3）Et al; inhibitionVEGFBinding to its receptor; inhibitionVEGFOf receptor phosphorylation.ERK-1/2It can inhibit apoptosis and promote cell growth,ERK-1/2The activation of this process can be caused by signalingVEGF mRNAOf overexpression, whereasERK-1andERK-2Activation of receptor enzymes requires divalent metal ions.EGCGChelatable divalent metal cation blockERK-1andERK-2Activation of, which in turn inhibitsVEGFAnd ultimately inhibit angiogenesis^[55]。EGCGCan significantly inhibit transcription activating factors（Stat3）The activity of theVEGFOfmRNAAnd protein expression were affected in a dose-dependent manner^[56]. in addition,VEGFThe signaling process of can form a multicomponent complex, causing protein kinaseB（PKB, also known asAkt）Activation of the pathway, which in turn induces cytokinesIL-8Expression and promote the proliferation of vascular endothelial cells. ifPKBInactivation of the pathway will severely inhibit its phosphorylation, and then inhibitVEGF mRNATranscription of^[57]。Rodriguezetc.^[58]The study found that,EGCGCan inhibitVEGFIt binds to its receptor, affects the formation of multiple complexes, and realizes thePKBPathway inhibition, and will be downregulatedIL-8.

Studies have shown that EGFR（EGFR）YesVEGF（EGF）EGFRAfter signaling pathway, downstream factors phosphorylate, leading to nuclear transcription factorsActivator protein-1（AP-1）Overexpression, which in turn combinesVEGFAnd make it activated^[59],EGCGTargetingEGFRSignaling pathway is of great significance for inhibiting angiogenesis, preventing and treating cancer.Research shows thatEGCGCan be adjusted byWnt/HhSignaling pathway downregulationCyclinD1、c-myc、EGFRTo inhibit hepatocarcinogenesis^[60]. the above research shows that,EGCGMay be down regulated byEGFRTo inhibit the expression ofVEGFAnd finally inhibit angiogenesis of cancer tissues.

1.4  Induction of cancer apoptosis

Apoptosis is considered to be a normal biological phenomenon. Apoptosis is an important process to maintain the normal physiological balance of the body. It is activated under the induction of specific endogenous and exogenous signals. It is a programmed death that occurs under the fine regulation of the intracellular apoptosis system. It can effectively remove unnecessary or damaged cells and plays an important role in the development of the body. One of the causes of malignant tumors is that tumor cells lose the ability of spontaneous apoptosis, so one of the most effective anti-cancer ways may be to induce apoptosis of tumor cells. At present, most chemotherapeutic drugs are used to eliminate tumor cells by inducing apoptosis.EGCGIts anti-tumor effect is related to its induction of apoptosis. The specific pathway of its induction of tumor apoptosis is related to cell type, state, effector activity and function in signal pathway, etc.

1.4.1  Mitochondrial pathway  The mitochondrial pathway plays an unusual role in apoptosis, and it is well known that mitochondria are the center of energy metabolism in eukaryotic cells and alsoROSMajor metabolic sites of^[61]Therefore, if mitochondria are damaged, the most direct result is the loss of normal cell function. Too manyROSWill change the permeability of mitochondria, resulting in water-soluble cytochromeC（CYC）Released to the cytoplasm, while the normal transmembrane potential of mitochondria（Δψ_m）Will also be destroyed and eventually activatedcaspaseCascade causes apoptosis^[62]。Lietc.^[63]The study found that in vitro useEGCGTreatment of liver cancerSMMC 7721After cells,CYCFrom the mitochondria to the cytoplasm,Δψ_mAttenuation,Bcl-2Changes in family proteins,caspase-3andcaspase-9Protein activation, and finally inductionSMMC-7721apoptosis。EGCGPro oxidant in cancer cells,EGCGBy promotingROSGeneration, causing oxidative stress leading to mitochondrial releaseCYC, and activatecaspase-3, eventually inducing apoptosis in endometrial cancer^[64]。

1.4.2  Bcl-2channel Bcl-2Is a common inhibitor of apoptosis gene (the inhibitor of apoptosis gene family hasBcl-2、c-mycEt al., the genes that promote apoptosis areFas、Bax、Bak、p53The overexpression of apoptosis can inhibit normal apoptosis and prolong cell life^[65], so that the cells that should have died continue to survive, and eventually lead to excessive cell proliferation and cancer. IntracellularBcl-2andBaxThe expression ratio of Bcl-2 and Bcl-2 determines whether the cell survives. If the ratio increases, the cell is not prone to apoptosis, and if the ratio decreases, it will cause apoptosis. stayEGCGFor cervical cancerHeLaIn the study of apoptosis,EGCGCan be adjusted byBcl-2Expression activation of family proteinscapsaseThe activity of theBaxThe protein expression was increased and down regulatedBcl-2Protein expression, makingBcl-2/BaxThe values decreased in a dose-dependent manner and increasedcapsase-3The expression level of apoptosis was finally induced^[66]。

1.4.3  Lysosomal pathway  Lysosomes have a large number of acid hydrolases, which can decompose macromolecules and non functional organelles into small particles and use them as new materials. . However, lysosomal membrane damage leads to lysosomal membrane permeabilization（LMP）Enhanced, resulting in the release of acidic substances and proteases, and excessive lysosomal membrane damage can lead to cell death.LMPMediated cell death is dependent on cathepsins rather thancaspase^[67]。EGCGAvailable through cathepsin-DCytoplasmic translocation（cathepsin-D cytosolictranslocation）And cytosolic acidification（cytosolicacidulation）LMP, and then release lysosomal proteases into the cytosol to induce human cervical cancerHeLacell death^[68]。ROSyesLMPMajor inducers of,EGCGThe pro oxidant properties of lead to intracellularROSForm, and then triggerLMPAnd cytoplasmic acidification, ultimately promoting apoptosis^[68]。

1.4.4  other EGCGIt can also play its role in inducing cancer apoptosis through some cell signaling pathways. ①p53Signaling pathway: during the normal cell cycle,p53Proteins by preventing cells fromG₁Phase inSTo cause damageDNAOr the chromosome is repaired; And whenDNAOr when the chromosome damage is too serious,p53It can trigger apoptotic mechanism to clear damaged cells, and finally play a regulatory role.EGCGBy inducingp53Activity and regulation ofp53Downstream targets such asBaxProtein et al., inductionp53Mediated cell death, which most studies have attributed top53Phosphorylation of serine residues of^[18]. ② death receptor pathway: death receptors are a group of cell surface markers, belonging to the tumor necrosis factor receptor superfamily（TNFR）, which, after binding to the corresponding ligand, can transmit apoptotic signals to the interior of the cell, resulting in activatedcaspaseProteases enzymolyze the corresponding substrates, eventually causing apoptosis,FasIs tumor necrosis factor receptor（TNFR）One of them,Fas-FasLigand system is one of the main pathways in the process of apoptosis^[69]. research shows thatEGCGThrough death receptor pathway and mitochondrial pathway, upregulationFasandBaxExpression, downregulationBcl-2Expression, activationcaspase-8、9, inducing lymphoma apoptosis^[70]. in addition,EGCGCan also regulate mitogen activated protein kinases（MAPK）Pathway^[71], phosphatidylinositol-3-Hydroxykinase（PI3K）/Aktaccess^[72], nuclear factorE2Correlation factor2（Nrf2）/Antioxidant response element（ARE）signaling pathway^[73]、Wntaccess^[74]andNotchaccess^[75]Other signaling pathways, such as affecting gene expression or protein phosphorylation, affect cellular functions, and ultimately induce tumor apoptosis.

1.5  adjustmicroRNAExpression levels of

MicroRNAIs a class of22～23Endogenous noncoding single strand consisting of nucleotidesRNAMolecules, which can interact with target genes3’Incomplete complementary pairing of noncoding regions, thereby regulating gene expression, leads tomRNA. Currently, more than2 000speciesmicroRNAControlling about1/3Human genes^[76]。MicroRNAIt is conserved in organisms and participates in a variety of pathological and physiological processes. Studies have found that it is closely related to the occurrence and development of tumors^[77]It is found in many human cancer types that some tumor suppressor or oncogenic related genes are dysregulated,microRNACan target these genes^[78]. numerousmicroRNAIt can affect some carcinogenesis processes, such as cell proliferation and differentiation, apoptosis and metastasis, and the generation of cell drug resistance,microRNABecome an important target of tumor therapy, drug regulationmicroRNAIt has become an emerging hot field in cancer research.MicroRNACan exert tumor suppressive or carcinogenic activity, i.emicroRNACan be classified as tumor suppressivemicroRNAAnd carcinogenicitymicroRNA。

EGCGAdjustable multiplemicroRNAThereby exerting its anticancer activity. Most of the current research is usingEGCGUp regulation of tumor suppressormicroRNAExpression of. Research findings in non-small cell lung cancerA549/CDDPIn cells, tumor suppressivemiR-485The expression of the overexpressedmiR-485Can reduceA549/CDDPStem cell properties,EGCGUpregulatedmiR-485, thereby inhibiting theA549/CDDPStem cell properties^[79]. insulin like growth factor-2Binding protein（IGF2BPs）Is a carcinogenicRNABinding protein, study foundIGF2BPsOverexpressed in hepatoma cells, which was recently confirmedIGF2BPsIs tumor suppressivemiR-1275Direct targets of.EGCGTreatment of HCC cells could significantly up regulatemiR-1275Expression, thereby inhibitingIGF2BPs mRNAexpress^[80]。EGCGBy upregulating tumor suppressormiR-1It can also inhibit the growth of osteosarcoma cells by up regulating the tumor suppressormiR-126Osteosarcoma apoptosis induced by the expression of^[81-82]。EGCGAfter treatment of prostate cancer cells, carcinogenicitymiR-21andAR(androgen receptor) signaling is inhibited, while tumor suppressivemiR-330The expression was upregulated, ultimately inhibiting prostate tumor growth^[83]。EGCGCan also downregulate carcinogenicitymicroRNATo exert anticancer effects, such asEGCGCan downregulate liver cancerHepG2Carcinogenicity in cellsmicroRNA（miR-30、miR-453）Et al^[84]。EGCGCan also downregulate non-small cell lung cancerA549Carcinogenicity in cellsmiR-98-5p, which causes the sensitivity of cisplatin to these tumor cells and plays an auxiliary sensitizing role^[85]。EGCGCombined with tretinoyl phenamine, it can downregulate some carcinogenicity in human neuroblastoma cellsmicro RNA（miR-92、miR-93、miR-106b）Expression of^[86]。

2  improveEGCGStrategies for bioavailability

EGCGIt has great potential in cancer prevention and treatment, but its low bioavailability, easy decomposition in physiological environment and slow absorption in vivo limit its role in clinical practice.EGCGThe oral bioavailability of is affected by many factors, such aspH, biological metabolic transformation, metal ions, temperature and oxygen concentration, etc^[84]Therefore, it is urgent to take measures to improveEGCGThe oral bioavailability, stability and therapeutic effect of. The current strategies mainly include:（1）Designing and developing effective delivery systems, such as nanoparticles, this method helps to improveEGCGThe bioavailability and availability of; （2）EGCGThe combination with other drugs and treatments produces more effective therapeutic effects than the use of drugs alone; The（3）Structural modification, synthesis more based onEGCGTo find more effective, stable and specific active molecules.

2.1  Nanoparticles

In recent years, the development of nanomaterial technology has made full use ofEGCG . After nano encapsulation, nano scaleEGCGOrdinary particlesEGCGIt has greater advantages. It can not only improve its fat solubility, stability and antioxidant properties, but also has the advantages of targeted delivery, slow-release drugs, prolonging half-life and reducing toxic and side effects. EGCGThere are mainly nanoparticles with metal as carrier, nanoparticles with polymer as carrier, nanoparticles with liposome as carrier and nanoparticles with other carriers.

2.1.1  Metal nanoparticles  Gold nanoparticles are the most studied metal nanoparticles. They have many characteristics, such as small size, can penetrate tissues and aggregate in tumor sites, and have optical properties, which can be used for photothermal anticancer therapy^[87]. nano gold particles andEGCGCombined treatment of cancer has obvious effect. In addition,EGCG-Silver Nanoparticles^[88]andEGCG-Nano cadmium particles^[89]Also developed.

2.1.2  Polymeric nanoparticles  Polymeric nanoparticles are solid structures composed of high polymers, which are especially suitable for drugs with poor water solubility. polymerEGCG. Polymeric nanoparticles can release therapeutic drugs through lymphocytes to protect them from hepatic metabolism, and can also be highlypHValue and enzyme in the environment to protect drugs to produce stable efficacy, but also has the characteristics of high permeability. Common packaging materials include chitosan and polylactic acid（PLA）, polyethylene glycol, poly (lactic co glycolic acid)（PLGA）And gelatin et al.

2.1.3  Liposome nanoparticles  Liposomes are multi-layered vesicles naturally formed by the dispersion of phospholipid bilayer in water. This structural property enables the encapsulation of lipophilic and hydrophilic drugs. Liposomes have the characteristics of biodegradability, low toxicity, targeting and sustained release. Research shows thatEGCGThe anticancer effect of liposomes was significantly better than that ofEGCG。

2.1.4  Other nanoparticles  At present, some other types of materials are also used inEGCGDesign of nanoparticles, such as carbohydrates and proteins.

Different types of nanoscaleEGCGThe anticancer activity of1。

2.2  Combined action with other substances

At present, the most important cancer treatment is chemotherapy, but the side effects of some chemotherapy drugs have greatly reduced people's quality of life. Therefore, it is urgent to develop chemotherapy drugs with low side effects, and another effective way is to find drugs with synergistic effects to reduce the side effects of chemotherapy drugs.EGCGIt has the advantages of high safety, easy access, multi-target and multi-channel, which makes it a better choice for adjuvant treatment of cancer.EGCGCombined with other anticancer drugs or cancer treatment methods, it can produce synergistic effects, reduce toxic and side effects and reduce drug resistance (table2）。

EGCGIt can be used as an adjuvant to synergize with a variety of anticancer drugs or therapeutic means, such as aromatic retinoidsAm80, doxorubicin, paclitaxel, docetaxel, noninvasive low-intensity pulsed electric field（PEF）And radiotherapy, etc. Chemotherapy often causes gastrointestinal toxicity, nephrotoxicity, cardiotoxicity, and pulmonary fibrosis,EGCGCombined chemotherapy can reduce the side effects of anticancer drugs, such as cisplatin, trifluoridine and doxorubicin. Drug resistance is a typical obstacle to cancer treatment,EGCGAnother important role in the combined use of drugs is to reduce the drug resistance of cancer cells, such as tamoxifen and oxaliplatin. However,EGCGCombined with anticancer drugs may also produce effects that reduce anticancer efficacy (table2）, indicating that green tea products should be banned during these drug treatments.

EGCG.EGCG The synergism with other substances or therapeutic means is also achieved by interfering with the growth of tumor cells, inducing apoptosis and acting on signaling pathways and other important mechanisms, and the synergism of different modes of action provides a new idea and theoretical basis for the treatment of cancer.

2.3  Structural modification

EGCGThe molecular structure contains multiple active phenolic hydroxyl groups, which are prone to deprotonation and rapid decomposition in neutral or basic media^[115], which makes it have disadvantages such as poor fat solubility, low bioavailability, easy decomposition under physiological environment, slow absorption in vivo, etc., which seriously reduces its biological activity and utilization rate, which seriously limitsEGCGApplication and development of. With the deepening of the research, researchers found that after a certain structural modificationEGCGThe derivatives have better stability, bioavailability is also significantly improved, and the introduction of new groups endows new physiological functions, thus expanding theEGCG. at presentEGCGThe molecular structure modification methods are mainly divided into2; The second is water-soluble derivatization modification, mainly including glycosidation.

EGCGThe molecule is rich in hydrophilic hydroxyl groups, so it shows poor lipid solubility, making it difficult to penetrate the double lipid layer structure of the cell membrane, thus reducing theEGCGPhysiological activity of^[116]. lipid soluble derivatization modification is mainly to connect lipophilic groups toEGCG, improving its fat solubility. Acetylation is carried out using acetyl groupsEGCGOf molecular modification, thereby improvingEGCGFat solubility, stability and bioavailability. wholeAcetylated epigallocatechin gallate(acetylated EGCG,AcEGCG）, inHeLaAssay findings in cellsAcEGCGThe anticancer activity ofEGCG, andAcEGCGCombined with doxorubicin can significantly improve the inhibitory effect of doxorubicin on cancer cells^[117]. methylation modifications areEGCGSome or all of the phenolic hydroxyl groups are converted into methyl ether to produce a series of derivatives. Research shows thatEGCGAfter the hydroxyl group of the derivative was replaced by a more stable methoxy group, its stability and lipid solubility were improved, which further improved the bioavailability and bioactivity of the derivative^[118]。

EGCGThere are many hydrophobic benzene rings in the molecule, which affect its water solubility. At present, the general method is to use glycosidic modification to connect hydrophilic monosaccharide molecules toEGCGMolecularly, in order to improveEGCGIts water solubility and metabolic activity in human body.EGCGAfter glycosidation modification, its water solubility was improved50～100Times, the sweet taste of glucosidogen can be reducedEGCGThe astringent taste, its antioxidant capacity was not affected and its stability was improved, which isEGCGProvided a theoretical basis for the study of oral utilization of^[119]. in addition, prodrugsEGCG（peracetate-protectedEGCG，pro-EGCG）Through the ethyl acetate group pairEGCGEthyl peracetate protectedEGCG^[120]. found in simulated body fluid environmentpHvalue8Left and right media（RMPI）In,pro-EGCGThe stability ofEGCGOf6times^[120]Studies have shown that in the role of breast cancerMDA-MB-231Cells,pro-EGCGthanEGCGWith more significant inhibition^[121]。

3  expectation

The negative impact of excessive use of chemicals on human health and survival has gradually expanded, resulting in the increasing incidence of cancer in contemporary society. All kinds of cancers have become the number one killer of human health. Traditional treatment methods are not only expensive but also cause side effects to varying degrees, affecting the quality of life of patients^[122-123]. natural productsEGCGIt has attracted attention because of its small side effects and good anticancer activity. With the deepening of research,EGCGThe anticancer activity of was gradually found, as shown in Fig1It can inhibit tumor cell cycle, inhibit tumor angiogenesis, induce cancer apoptosis and regulatemicroRNA.

At present, the strategies of using oxidative stress to cope with cancer mainly include: enhancing endogenous antioxidant capacity at the stage of cancer prevention, and improving it at the stage of cancer treatmentROSLevels cause cancer cell death, with antioxidant and pro oxidant propertiesEGCGThis strategy is well adapted. High concentration ofEGCGIt is a current trend to treat cancer, however, due to the difference of cell types and cellular conditions, depending onEGCG. In addition,EGCGThe mechanism from Pro survival to pro apoptosis is still unclear. Some studies have pointed out that this may be related to rapid cell metabolism and unregulated signaling pathways, which areEGCGInduced productionROSProvides a special microenvironment^[31]This hypothesis still needs further research and demonstration.EGCGThe anticancer effect has the characteristics of multi-pathway and multi-target, and there are in each pathwayEGCGActionable targets, whileEGCGThe specific mechanism acting on some pathways is still unclear. In the future, it is necessary to construct a more perfect simulation environment to further study its systematic mechanism of action in the human body. It is also necessary to explore the mechanisms that can beEGCGNew pathways of regulation, and then draw a more perfectEGCGMediated anticancer cell signaling pathway map, providing more possibilities for targeted therapy. In addition,EGCGWith cell type - and environment specific responses, therefore, more responses toEGCGPhysiological concentrations of responsive molecular targets or biomarkers.

EGCGThe study of molecular mechanism provides a theoretical basis for its practical anticancer application, howeverEGCGThere is a problem of low bioavailability in application. To solve this problem, relevant research has made some progress, which is partly due to the development of nanoparticle carrier system,More importantly, targeted therapy based on nanoparticles is a promising therapeutic strategy to overcome the poor specificity of traditional chemotherapy drugs. Active targeted therapy by adding a specific ligand to nanoparticles is expected to become the most effective treatment. In terms of biological targets, tumor associated antigens seem to be better targets for therapeutic intervention. The clinical application of these bioconjugates is expected to be realized soon. EGCGCarrier, in order to explore the pharmacokinetics, therapeutic effect and targeting of carrier drugs. In addition, the encapsulation system supported by nanotechnology has local excess effect and related safety problems. Therefore, it should be further explored to determine the content ofEGCGThe relationship between the actual dose and its actual pharmacological effect. Chemotherapy and radiotherapy in the treatment of cancer have time-dependent and various side effects, and even lead to the termination of treatment. One strategy to overcome this defect is to develop more compatibleEGCGCombined new combination therapy to reduce the side effects of conventional anticancer drugs or methods. In addition, the use ofEGCGProdrugs such aspro-EGCGIt can help solve the problem of low bioavailability, but further research is needed. Although molecular modification can obtain the established target products, the internal relationship between the change of spatial structure and efficacy still needs further study. Future studies need not only to fully elucidateEGCGMore strategies need to be designed to develop applicationsEGCG, making it a better cancer prevention and treatment drug.

References (omitted)  

Come   Source:Lixiaoyang, wuzhiping, wangmengxin, Bai Xueyan, huangliqing, zhuxiaoyan, hanbaoyu