Research Progress on anti-tumor mechanism of active ingredients of Astragalus membranaceus

Malignant tumor has always been a major disease that puzzles human life and health. In the process of tumor development, it will make full use of the tumor microenvironment and the cellular tissue conditions of the body to achieve further metastasis and spread. The occurrence and development of malignant tumor are often accompanied by complex pathogenesis, such as inflammation and oxidative stress, microenvironment and cell perturbation, obesity and environmental factors are all risk factors that lead to malignant tumor^[1]. chemoradiotherapy^[2]And surgical treatment can curb malignant tumors to some extent, but it also can induce multidrug resistance（multidrug resistance，MDR）^[3], cardiac injury^[4]And the risk of psychological disorders, but also has a high risk of recurrence. Therefore, the research and development of new treatment schemes and new drugs for malignant tumors is particularly important.

Traditional Chinese medicine therapy has accumulated rich experience in tumor treatment. With the continuous development of traditional Chinese medicine research in China, a large number of achievements have been obtained in the research of traditional Chinese medicine, its components and its active ingredients with anti-tumor effect. ^[5], Qi tonifying and astringent astringent herbs and their formulas are often used in the treatment of tumors^[6-7], of which Astragalus membranaceusAstragali Radix. Modern medical research shows that Astragalus polysaccharides, flavonoids, saponins and other active ingredients rich in Astragalus can effectively inhibit tumor metastasis and spread, including astragalus polysaccharides, formononetin, calycosin isoflavones, astragaloside IV, astragalosideII andAstragalosideIII It has been reported in recent years and has strong antitumor activity. In addition, HuangThe combination of stilbene and other drugs can improve the anti-tumor effect or reduce the toxic reaction, such as Astragalus membranaceus-Bevacizumab, Astragalus-Apatinib, Astragalus membranaceus-Doxorubicin, Astragalus membranaceus-Rhizoma curcumae, Radix Astragali- Rhizoma Curcumae-5-Fluorouracil, Astragalus-Rhizoma Curcumae-Flea rest horn, Astragalus membranaceus-Rhizoma Curcumae-.

This paper summarizes the active ingredients of Astragalus membranaceus, the anti-tumor effect of Astragalus membranaceus combined with other drugs and its molecular mechanism, and discusses the application rules and ideas of Astragalus membranaceus in anti-tumor, so as to provide a theoretical reference for the development and utilization of Astragalus membranaceus resources and the research of anti-tumor clinical therapy.

1 Antitumor effect and molecular mechanism of active components of Astragalus membranaceus

1.1 Astragalus polysaccharide

Astragalus polysaccharide is the main active ingredient in the dry root extract of Astragalus membranaceus. Studies have shown that Astragalus polysaccharide can regulate the inflammatory cascade^[8], treatment of diabetes and its complications^[9], regulating immunity^[10], anti-tumor, hepatoprotective and cholagogic^[11]. In recent years, a large number of experimental results have confirmed that Astragalus polysaccharide can inhibit the proliferation and metastasis of tumor cells through a variety of mechanisms.

1.1.1 Regulating cell cycle and promoting early apoptosis of tumor cells . Yanlijun et al^[12]The effect of Astragalus Polysaccharides on colon cancer was studiedSW620It was found that Astragalus polysaccharide can effectively promote cell cycle arrest inG₂/MPhase, upregulation of cytochromeC, caspase-3（cysteine aspartase-3，Caspase-3）、Caspase-9andBLymphoblastoma-2correlationXProtein（B-cell lymphoma-2 associated X protein，Bax）Expression of, downregulatedpro-Caspase-9AndBLymphoblastoma-2（B-cell lymphoma-2，Bcl-2）The expression of Astragalus polysaccharide can be induced by regulating the cell cycle and controlling the mitochondrial pathwaySW620Cells tended to undergo early apoptosis. nuclear factor-κB（nuclear factor-κB，NF-κB）It is an important transcription factor affecting tumor cycle and apoptosis. It is the collective name of an evolutionarily highly conserved and structurally related transcription factor family, which plays an important role in tumor differentiationPlay a key role in growth, apoptosis and metastasis,Wuetc.^[13]Studies have confirmed that Astragalus polysaccharides can be reduced byNF-κBPathway inhibition in non-small cell lung cancerA549andNCI-H358Cell proliferation, given2Cell linesNF-κBAgonists can attenuate the inhibitory effect of Astragalus Polysaccharides on tumor cells, on the contrary, givenNF-κBThe inhibitor can enhance the inhibitory effect of Astragalus Polysaccharide on tumor, which fully confirmed that Astragalus Polysaccharide andNF-κBCorrelation of interactions.

1.1.2 Improve immune function and inhibit immune response The inhibitory immune response of inflammation and tumor microenvironment often accompanies and induces the proliferation and metastasis of tumor cells. Astragalus polysaccharide can improve immune function and inhibit immune response^[14-15]Stimulate natural killer cells and macrophages to play an immune role, induce autophagy of tumor cells, reduce local inflammation, regulate the tumor microenvironment and other ways to control the further development of tumor. Inflammatory cytokine interleukin in the proliferation of rectal cancer-17（interleukin-17，IL-17）And transforming growth factorβ1（transforming growth factor-β1，TGF-β1）IL-17andTGF-β1It can effectively control the inflammation of tumor microenvironment and the formation of neovascularization, thereby changing the regulatory properties of tumor surrounding environmentTCells（regulatory T cell，Treg）It can inhibit tumor proliferation, invasion and metastasis. Zhaoyuanyuan et al^[16]fromIL-17andTGF-β1Start withELISADetection of rectal cancer by HPLCHCT-116Transplanted tumor model miceipAstragalus polysaccharide21 dIn the posterior serumIL-17andTGF-β1The results confirmed that Astragalus polysaccharide could significantly reduce the serumIL-17andTGF-β1.Elhametc.^[17]Through cervical cancerHeLaCell coculture of human peripheral blood mononuclear cellsPBMCsTo explore the immunomodulatory effect of Astragalus Polysaccharide on tumor microenvironment, the results showed that Astragalus polysaccharide could promote the immune regulation of tumor microenvironmentHeLaCell coculturedPBMCsCell proliferation, thereby significantly reducingIL-10andTGF-βTo regulate the immune response and inhibit the proliferation of tumor cells.Lietc.^[18]To confirm the effect of Astragalus Polysaccharides on the microenvironment of human hepatoma cellsTregEffect of cell function, after astragalus polysaccharide administration, in the study tissue samplesTregTypical markers of cellsCD4、CD25andCD127The expression of winged helix transcription factors was analyzed（forkhead box P3，FOXp3）mRNA, and the cell supernatant was detectedIL-4、IL-10、γ（interferon-γ，IFN-γ）And stomatal cell-derived factors- 1（stomal cell-derived factor-1，SDF-1）CD4⁺CD25⁺TregCells, and this inhibition is through the reduction ofFOXp3In addition, astragalus polysaccharide may block theSDF-1（C-X-CMotif) receptors4 [chemokine (C-X-C motif) receptor 4，CXCR4]/Chemokines（C-X-CMotif) ligand12 [chemokine (C-X-C motif) ligand 12，CXCL12]Pathway pairTregCell migration was inhibited, which indicated that Astragalus polysaccharide could inhibitTregCell immunosuppression, thereby inhibiting the development of tumor and improving the survival rate of liver cancer. In conclusion, astragalus polysaccharide can regulate immune function and inhibit tumor cell proliferation by activating anti-tumor related immune cells, promoting anaerobic metabolism of tumor microenvironment, and restoring cytokine balance in tumor microenvironment^[19-20]。

1.1.3 Reversal or escape of multidrug resistance（multiple drug resistance，MDR） In cancer patients receiving chemotherapy, most treatment failures and deaths are due toMDR^[21]Therefore, modern medical research focuses more on the ability to reverse or escapeMDRThe experiment confirmed that Astragalus polysaccharide can not only improve the response of tumor to chemotherapy drugs to achieve reversalMDRAt the same time, it can also reduce the toxic reactions caused by chemotherapy drugs^[22-23]Astragalus polysaccharides can inhibitTGF-β1Overexpression mediated epithelial-Mesenchymal transformation, thereby inhibiting overexpressed cisplatin resistantA549Proliferation of cell transplanted tumor^[24]。Songetc.^[25]In vitro experiments confirmed that Astragalus polysaccharide could not only independently induce gastric cancerGCapoptosis， It can also enhance the effect of doxorubicin onGCThe pro apoptotic effect of Astragalus Polysaccharide shows that Astragalus polysaccharide can play a role in chemosensitization to a certain extent. In addition, for those with high drug resistanceHL-60/ACell lines, astragalus polysaccharides can induceHL-60/AApoptosis andCaspaseCascade activation, significantly reducing multidrug resistance related proteins（multi-drug resistant associate protein，MRP）^[26]Astragalus polysaccharides can also improve the sensitivity of tumor cells to chemotherapy drugs such as apatinib, thus escapingMDR, improve the anti-tumor effect^[27-28]。

The anti-tumor mechanism of Astragalus polysaccharide is shown in table1。

1.2 Flavonoids

In recent years, studies have confirmed that Astragalus flavonoids alone or in combination with cisplatin can effectively inhibit the proliferation and transformation of lung cancer cells, liver cancer cells, erythroleukemia cells and laryngeal squamous cell carcinoma cellsshift^[29-31]And Astragalus flavonoidsFormononetin（formononetin），Calycosin（calycosin）, calycosin isoflavoneGlycoside, formononetinAmong them, formononetin and calycosin isoflavones have been reported more in recent years, which have significant antitumor activity and molecular mechanism research is more in-depth.

1.2.1 Formononetin In recent years, the antitumor activity of formononetin has been confirmed by a large number of research results,Jiangetc.^[32]Comprehensively analyzed the tumor types and related pathways targeted by formononetin. In addition, recent studies have found more relevant molecular mechanisms of formononetin inhibiting tumors. This paper classified them, as shown in Fig1Shown in.

.Parketc.^[33]Formononetin against ovarian cancerES2andOV90The results showed that formononetin could block the cell cycle inG₀/G₁Phase promotes the apoptosis of ovarian cancer cells, and the related mechanisms involved includeERK1/2、P90RSK、Akt、P70S6KProteins and ribosomal proteinsS6Decreased phosphorylation of, andES2andOV90In cellsp38The research results also confirmed that formononetin can act on the mitochondria of ovarian cancer cells to lose their membrane potential and inhibit the production of reactive oxygen species. At the same time, formononetin combined with pharmacological inhibitors（LY294002orU0126）Can synergistically inhibit2The proliferation of breast cancer cells enhances the anti-tumor effect.Huangetc.^[34]To explore whether the proapoptotic effect of formononetin on androgen independent prostate cancer is related to pancreatic isletsVegan like growth factor-1（insulin-like growth factor，IGF-1）/ IGF-1Receptors（IGF-1R）The results confirmed that when the concentration of formononetin was greater than12.5 μmol/LTime rightPC-3Cells have significant inhibitory effect, and its effect onBaxThe upregulation ofpIGF-1RThe downregulation of formononetin was dose-dependent, which indicated that formononetin could inhibitIGF-1WithIGF-1RThe combination of the two eventually leads to the proliferation inhibition of tumor cells.Lietc.^[35]Study on formononetin inhibiting prostate cancer from the perspective of cell cycle arrest mechanismPC-3Cell mechanism, the results showed that formononetin could lead toPC-3The cell cycle was significantly arrested atG₁Period, and make itAktThe level of phosphorylation decreased, and formononetin significantly downregulated cyclins in a dose-dependent mannerD1andCDK4Of the expression level, and finally inhibitedPC-3Proliferation of cells.

Formononetin can regulate the tumor microenvironment and inhibit tumor angiogenesis and metastasis.Zhangetc.^[36]To study the anti-tumor effect of formononetin in vivo and its effect on tumor tissue in nude mice model of cervical cancerHIF-1αandVEGFProteins andmRNADuring the in vivo experiment, it was found that the tumor inhibition rate of cisplatin group was56.24%The tumor inhibition rate of formononetin group was50.17%However, the cisplatin group had obvious adverse reactions of decreased appetite and depressed mood, while the formononetin group had a good survival condition, and the formononetin group was significantly lower than the positive control group in tumor tissueHIF-1αandVEGFOf proteins andmRNAThe expression level was significantly reduced（P＜0.05）, this result confirms that formononetin may inhibitHIF-1αandVEGFIt can reduce the stability of cellular oxygen and hypoxia resistance in the hypoxic tumor microenvironment, and inhibit tumor angiogenesis, so as to achieve the effect of inhibiting cervical cancer. Although the inhibitory effect is weaker than that of cisplatin, the adverse reactions of model mice are small.

Formononetin can inhibit tumor development and metastasis by regulating tumor marker genes.Wangetc.^[37]In vivo experiments proved that formononetin can effectively inhibit gastric cancerSGC-7901andMGC-803Growth and metastasis of cell lines, significantly upregulating hallmark oncogenesmicroRNA-542-5pAt the same timeWuetc.^[38]Found that formononetin can regulatemiR-21Human mediated10Phosphatase and tensin homologous genes deleted on chromosome（phosphatase and tensin homologue deleted on chromosome ten，PTEN）/AktPathway inhibits the proliferation and metastasis of human bladder cancer cells, similar to targetingmicroRNA-542-5pandmiR-21.

Formononetin is also an excellentMDRReversal agents.Lietc.^[39]Studies have shown that formononetin can inhibitmiR-199a-3pMake its downstream target mammalian target of rapamycin（mammalian target of rapamycin，mTOR）Restore to the parental level, thereby inhibiting paclitaxel resistantMDAMB-231Autophagy, reaching reversalMDRIt can inhibit the proliferation of breast cancer, so formononetin and paclitaxel combined with anti breast cancer can reduce the chemotherapy failure caused by drug resistance, and this experiment confirmed that the anti-tumor effect of the combined treatment group was more significant. In addition to the combination with paclitaxel, formononetin can also be combined with epirubicin to improve the treatment of cervical cancerHeLaThe mechanism of cell inhibition is to increase the level of reactive oxygen species, reduceMDRrelated geneMRP1andMRP2At the same time formononetin activated the mitochondrial and death receptor apoptotic pathways and enhanced the effect of epirubicin onHeLaCell inhibition^[40]。

1.2.2 Calycosin Calycosin has a strong inhibitory effect on breast cancer, rectal cancer, cervical cancer, thyroid cancer, liver cancer and other malignant tumors, as shown in Fig2Shown in. In this paper, the tumor and related pathways targeted by calycosin were sorted out. The results showed that the anti-tumor pathways of calycosin involved apoptosis, cell cycle, autophagy, immunity and inflammation.
Calycosin has shown significant inhibitory effects against many female high-risk tumors, such as calycosin can promote transcription factorsTFEBAutophagy pathway of nuclear translocation cells inhibits thyroid cancerTPC-1Cell proliferation, and this inhibitory effect showed obvious dose correlation^[41]。Tianetc.^[42]Through research, it was found that calycosin canmiR-375-ERαFeedback loop inactivation mediates estrogen receptor positivityER⁺（MCF-7andT47D）The proliferation of breast cancer cells was inhibited;lncRNAsMicroarray results confirmed that calycosin could upregulate long-chain noncodingRNA（lncRNA）WDR7-7The expression of suppressor estrogen receptor negativeER⁻（MDA-MB-468andSKBR3）AndER⁺（MCF-7andT47D）Breast cancer cell proliferation, in addition, calycosin also upregulatedTTC21B-AS1andCTA-384D8this2specieslncRNAOf expression, butWDR7-7With the highest average growth rate,WDR7-7yesGProtein coupled estrogen receptor30（G protein conjugated estrogen receptor 30，GPR30）Target of,GPR30It can be activated by estrogen and plays an important role in the occurrence and development of estrogen related tumors, such as breast cancer, cervical cancer and ovarian cancerER⁻andER⁺In breast cancerWDR7-7andGPR30All showed negative correlation, soWDR7-7andGPR30It may play a role with the traditional estrogen receptor to participate in the process of calycosin inhibiting breast cancer.Zhangetc.^[43]It was found that calycosin could significantly up regulate the tumor suppressor of cervical cancer cellsmiR-375And increase lactate dehydrogenase（lactate dehydrogenase，LDH）miR-375Gene can significantly reverse the inhibitory effect of calycosin on cervical cancer cells, somiR-375Gene may become an important marker to judge the efficacy of calycosin in the treatment of cervical cancer.

In many discussions on the anti-tumor effect of calycosin,Zhangetc.^[44]Put forward the theory that calycosin has a dual role in the occurrence and development of pancreatic cancer. The experimental results show that on the one hand, calycosin can regulatep21Wide type53Activator1（wide-type 53-activated factor 1，Waf1）/Cyclin dependent kinase interacting protein1（cyclin-dependent kinase interacting protein 1，Cip1）Pathways promote cell cycle arrest, as well as induceCaspaseDependent apoptosis achieves inhibitionMIA PaCa-2The effect of cell proliferation, on the other hand, calycosin can lead toRasEffector protein（Ras effector protein，Raf）/（mitogen-activated protein，MEK）/Extracellular regulated protein kinase（extracellular signal- regulated kinase，ERK）Activation of pathways and promotion in the tumor microenvironmentM2Polarization of tumor associated macrophages, which on the contrary will make them have the potential to promote tumor cell metastasis and invasion. This dual effect is associated with the upregulation of calycosinTGF-β1Because during the development of pancreatic cancerTGF-β1It can play a dual role as a tumor suppressor and tumor promoter.

.Tanetc.^[45]Through human osteosarcoma samples and animal experimental studies, it was found that calycosin could up regulateCaspase-3And tumor proteins53（tumor Protein p53，TP53）Expression of, downregulatedXLinked inhibitor of apoptosis protein（X-linked inhibtor of apoptosis protein，XIAP）Thus inhibiting the development and metastasis of osteosarcoma,Caspase-3It is a classical cell death protease. Once inhibited, it will lead to enhanced cell proliferation, metastasis and invasion,TP53Involved in cell growth, survivalDNARelated regulatory processes of stability and cytoprotection, whileXIAPTherefore, calycosin can inhibit the proliferation and metastasis of osteosarcoma by controlling the expression of multiple tumor associated proteins.

1.3 Astragalus saponins

astragaloside iv IV^[46-47], astragalosideⅡandIIIIt is a proven anti-tumor effective component of Astragalosides. MDRAnd regulation of immunity.

In the regulation of cell cycle, reversal and escapeMDR,Zhengetc.^[48]Astragaloside IV was studiedIVThe effect and molecular mechanism of improving the sensitivity of breast cancer to paclitaxel, the experimental results showed that astragaloside IVIVCan improveMCF-7andMDA-MB-231Cells as well as non neoplastic mammary epithelial cell linesMCF-10ASensitivity to paclitaxel, making it Pro apoptosis and arrestG₂/MThe cell phase effect was enhanced, while astragaloside IVIVBy inhibiting caveolin-1（caveolin-1，CAV-1）Triggering endothelial nitric oxide synthase（recombinant endothelial NOS，eNOS）/NO/Peroxynitrite anion（ONOO⁻）Pathway, leading to serious oxidative damage of tumor cells, and it can also improve the sensitivity of cells to paclitaxel.G₂/MPhase is a key transition point of the cell cycle, and the arrest of this cell cycle suggests that tumor cellsDNAMay be damaged and unable to enter the next cycle, whileCAV-1It is a stress-related tumor target, which has been confirmed to be closely related to chemotherapy resistance. Therefore, astragaloside IVIVIt can inhibit tumor by arresting cell cycle and escaping drug resistance,CAV-1It can also be used as astragaloside IVIVOne of the reference targets for the design of related antitumor agents. ^[46]Astragaloside IV was studiedIVCisplatin resistant mouse lymphocytic leukemia cell linesL1210/DDPThe results of cell inhibition experiments confirmed that the combination of astragaloside IVIVCan significantly improve the tumor proliferation inhibition rate, from8.83%Rise to16.74%And the level of reactive oxygen species showed a downward trend, which could also block the cell growth inSPeriod andG₂/MThe results of mechanism study confirmed that astragaloside IVIVBy adjustingp62-Nuclear factor erythroid2Correlation factor2（NF-E2-related factor 2，Nrf2）Pathway related genes, decreased theL1210/DDPThe oxygen free radical level of cells, thereby improving their sensitivity to cisplatin. Yueguijuan et al^[49]It was confirmed by transcriptomic technology that astragaloside IV can regulateWntandMAPKSignaling pathway reverses doxorubicin resistance.

In regulating immunity, Astragalosides have been proved to effectively regulate immune response, inhibit immune evasion and induce macrophage polarization, indoleamine2,3-Dioxygenase（recombinant indoleamine-2,3-dioxygenase，IDO）Induced immune tolerance in non-small cell lung cancer can be inhibited by astragaloside IVIVReversal, astragaloside IVIVCan be suppressed byIDOThereby inhibitingTregsThe expression activity of the cells, increasing cytotoxicityTLymphocyte activity, regulation of impairedTLymphocyte function, affecting immune escape in non-small cell lung cancer^[50]. research confirms^[51]Astragaloside IV can also enhance immune response and inhibit lungThe function of cancer cell proliferation and metastasis through the inhibition of immunoglobulin like transcripts4（immunoglobulin like transcript，ILT4）-PI3K/Akt-B7-H3Pathway, while astragaloside IV can induceM1T-type macrophage polarization initiates immune response and thus inhibits tumor cell proliferation^[52]. Wang Min et al^[53]EstablishedH₂₂Tumor bearing mouse model for evaluating astragalosideIITo splenic lymphocytesTh1Transcriptional levels of cell related factors and their effects onTh1andTregsEffect of Astragaloside on cell proliferationIICan promoteTh1Cytokines release, activate nuclear transcription factors, and enhance anti-tumor immune response, thereby inhibiting liver cancer in model miceH₂₂Proliferation of cells.Chenetc.^[54]Studies have confirmed that astragalosideIIIThe development of colon cancer can be inhibited by stimulating systemic immune regulation of natural killer cells. The mechanism pathways of Astragalus saponins against different tumors have the value of in-depth research, and a clear mechanism will be conducive to promoting the clinical application of Astragalus saponins and providing new ideas for anti-tumor treatment.

The anti-tumor mechanism of Astragalus saponins is shown in table2。

2 Anti tumor effect of Astragalus membranaceus combined with other drugs

2.1 Anti tumor effect of Astragalus combined with chemotherapy

A number of studies have shown that Astragalus membranaceus or its active ingredients combined with chemotherapy drugs can play a role of enhancing efficacy and reducing toxicity in the process of anti-tumor treatment. Paclitaxel has higher effective dose and greater toxicity in the process of anti-tumor treatment. In order to improve its anti-tumor effect and reduce adverse reactions, researchers put astragaloside IVIVIn combination with paclitaxel, studies have shown that both of them regulateSTAT3-NF-κBPathway improves the inhibitory effect on gastric cancer cells, and inhibiting this pathway can also reduce the resistance of tumor cells to cisplatin^[55]。Quetc.^[56]Studies have confirmed that astragaloside IVIVCan improveHepG2Cells andH₂₂Sensitivity of tumor bearing mice to cisplatin, inhibitionMDRRelated proteinsMRP2In addition, astragaloside IVIVCombined with cisplatin can also reduce liver and kidney injury caused by cisplatin^[57]. Zhang Zhihui et al^[58]In order to confirm that Astragalus can alleviate the adverse reactions of bevacizumab, oxaliplatin and capecitabine combination regimen in the treatment of metastatic colon cancer, we used2017—2021Admitted in70Patients with metastatic colon cancer were selected as the research object to explore the clinical therapeutic effect of Astragalus and bevacizumab combination therapy on elderly patients with metastatic colon cancer and its impact on tumor markers,70Patients were randomly divided into control group (bevacizumab combination therapy) and treatment group (Astragalus granule + bevacizumab combination therapy). The results showed that Astragalus granule could improve gastrointestinal discomfort and immune function produced by bevacizumab combination therapyCan be impaired, and the treatment group down regulated serum matrix metalloproteinase inhibitionagent-1（tissue inhibitor of metalloproteinase-1，TIMP-1）、MMP-7andp53The expression of antibody was significantly enhanced compared with the control group. In order to confirm that Astragalus polysaccharide can alleviate the immune injury caused by paclitaxel,Baoetc.^[59]（4T1）OfBALB/cThis hypothesis was verified in mouse models and cocultured cell models. In vitro experiments confirmed that Astragalus polysaccharide could inhibit the effect of paclitaxel on mouse monocyte macrophagesRAW 264.7（phospho-histone H2A，P-H2A）、PARP, cell cycle checkpoint kinase1（checkpoint kinase 1，Chk1）、p53andp21Up regulation of protein levels, andBcl-xLAnd myeloid leukemia-1（myeloid cell leukemin-1，Mcl-1）The protein level was down regulated, but it did not affect the effect of paclitaxel on4T1. Astragalus polysaccharide can also be combined with apatinib by inhibitingMMP-9andp-AktProtein expression enhances antitumor effects^[60]The compatibility of Astragalus membranaceus, astragaloside IV, astragalus polysaccharide and doxorubicin can alleviate cardiac toxicity^[61], reversalMDR^[62], improve the anti-tumor effect. The above experimental results show that the combination therapy of Astragalus membranaceus and its anti-tumor components with chemotherapy drugs has shown certain advantages in basic research and clinical observation, but the mechanism of its synergism and toxicity reduction still needs to be further explored.

2.2 Anti tumor effect of Astragalus membranaceus combined with other traditional Chinese medicines

Summarizing the compatibility rule of Astragalus membranaceus in anti-tumor in recent years, the author found that its main idea is to promote blood circulation, remove blood stasis, and replenish qi. In addition, the compatibility therapy of traditional Chinese medicine also takes into account the regulation of immunity, anti-inflammatory response and other aspects. Among them, the compatibility of Astragalus membranaceus and Zedoary Turmeric can effectively inhibit the metastasis and proliferation of colon cancer-The compatibility of Rhizoma Curcumae can replenish qi and break blood stasis, strengthen health and eliminate pathogens, promote water and eliminate accumulation, Astragalus membranaceus-Rhizoma curcumae, Radix Astragali-Rhizoma Curcumae-Paris polyphylla^[63]The compatibility can inhibit the growth of colon cancer tissue, and the main mechanism is to inhibit the metastasis of colon cancer by reducing the vascular endothelial permeability, regulateSDF-1/CXCR4/NF-κBSignaling pathway related protein expression and other pathways, but the inhibitory effect is relatively5-Fluorouracil weak^[64-65]In order to improve the anti-tumor effect, researchers combined traditional Chinese medicine with5-To explore the antitumor effect and mechanism of fluorouracil combination, Liang Li et al^[66]EstablishedCT26.WTOrthotopically transplanted tumor mouse model, confirming that Astragalus membranaceus-Zedoary turmeric and5-The combination of fluorouracil may be through downregulationCXCL10/CXCR3Axis, chemokine ligandL3（chemokine ligand 3，CCL3）/ChemokinesC-C-Elementary receptor5（recombinant chemokine C-C-motif receptor 5，CCR5）The expression of axis enhances the efficacy of anti colon cancer, but the optimal ratio of drugs still needs further exploration. Guowenhui et al^[67]The study found that Astragalus membranaceus-Curcuma combined5-Fluorouracil showed better anti-tumor effect than chemotherapy alone in the ectopic transplanted tumor mouse model, and5-Fluorouracil combined with high dose Astragalus-The average tumor mass decreased most significantly in the curcuma group, and the mechanism research results showed that the combined therapy could promote apoptosis, regulate tumor microenvironment immunosuppression, inhibit epithelial mesenchymal transition and inflammatory factors, and make the spleen tissue of model miceCD4⁺IL-17⁺The proportion of cells decreased,CD4⁺Foxp3⁺The proportion of cells increased and maintainedin vivoTh17/TregDynamic balance of. In addition, Astragalus membranaceus-Rhizoma Curcumae-Flea rest horn^[68]. However, based on the experimental results, it is not difficult to find that the effect of traditional Chinese medicine is weaker than that of chemotherapy drugs in the treatment of colon cancer. Therefore, the combination therapy of traditional Chinese medicine and chemotherapy drugs is worthy of further study.

Astragalus membranaceus-Angelica sinensis is common in traditional Chinese medicine and has high anti-tumor application value,Wuetc.^[69]Astragalus membranaceus was studied-The inhibitory effect of Angelica compatibility on lung cancer, through male transgenicC57BL/6Mice andCAnN.Cg-Foxn1^nuNude mouseLewisThe lung cancer model was used to investigate the inhibitory effect of water extracts of Astragalus membranaceus and Angelica sinensis at different doses on lung cancer, and the possible molecular mechanism was studied. It was found that Astragalus membranaceus and Angelica sinensis acted on lung cancer aloneLLCCells even when the mass concentration was higher than100 mg/mLIts cell inhibition rate is still lower than50%However, Astragalus and Angelica can effectively improveLPSInducedRAW264.7Phagocytosis of cells, the effect of Astragalus membranaceus-The proportion of Angelica sinensis is5∶1When reaching the platform level. In vivo experiments revealed that Astragalus membranaceus + Angelica sinensis had a significant effect onC57/BL6The mouse model has stronger antioxidant and anti-inflammatory effects, which can be regulated byTCellular immunity can inhibit tumor related inflammatory and oxidative reactions, and the combined application of traditional Chinese medicine can also down regulate the expression ofNF-κΒ、STAT3、HIF-1αandVEGF, and these results were not found inCAnN.Cg-Foxn1^nuThis shows that although the anti-tumor effect of Astragalus membranaceus + Angelica sinensis is not ideal, its anti-inflammatory and immune microenvironment regulating effects can be used in the adjuvant treatment of anti-tumorPlay a key role in treatment. In addition to the above compatibility groups, Astragalus membranaceus-Atractylodes macrocephala^[70]Astragalus membranaceus-Hedyotis diffusa^[71].

The above research shows that the compatibility of Astragalus membranaceus with other traditional Chinese medicines and combined chemotherapy drugs can play a greater role in anti-tumor effect, but the dose of the formula, the choice of compatible traditional Chinese medicines, the mechanism of action and the characteristics of the effect on various types of tumors need to be continued.

3 Conclusion and Outlook

Summarizing a large number of research results, it was found that Astragalus membranaceus, as a commonly used medicinal material for tonifying Chinese herbs and replenishing qi, its main active components astragalus polysaccharides, saponins and flavonoids can effectively inhibit a variety of malignant tumors such as gastric cancer, liver cancer, colon cancer, lung cancer and so on. The anti-tumor mechanisms of Astragalus membranaceus and its combination therapy mainly include:①Induce early apoptosis of tumor cells;②Arrested cells;③The immune system that regulates the body and tumor microenvironment;④;⑤ReversalMDR;⑥Inducing autophagy of tumor cells, etc. As the molecular mechanism of Astragalus membranaceus anti-tumor has been revealed, the multi-target, multi link and multi-level mechanism of traditional Chinese medicine has gradually emerged. However, in the anti-tumor research of Astragalus membranaceus and its components, in addition to the molecular mechanism research, the related research on its gene markers still needs to be carried out in depth, which is of great significance for the efficacy monitoring and the research and development of targeted agents.

At the same time, the author also believes that the combination of Astragalus membranaceus and its active components as Chemosensitizers and chemotherapeutic drugs is the key entry point of Astragalus membranaceus anti-tumor research, and the drug combination treatment scheme can play a role in enhancing efficiency, reducing toxicity and reversing from multiple pathwaysMDRAnd the role of regulating the immune microenvironment, but to play a better effect, the ratio of Astragalus membranaceus and other drugs in combination therapy needs to be explored in depth. The combination ratio may be different due to different tumor types, so the differentiated design of drug delivery scheme needs to be supported by rich randomized clinical trial results. In general, the role of Astragalus membranaceus in the field of anti-tumor needs a large number of scientific research conclusions as theoretical basis and guidance. Therefore, further research on the anti-tumor activity of Astragalus membranaceus and its components has important guiding significance for promoting the development and utilization of Astragalus membranaceus resources, the research and development of new anti-tumor drugs and clinical medication.

Pictures, references (omitted, see original magazine)

Come Source: xushiyi, liuxiubo, lujiaxin, zhangzhanping, yanxueying, Ma Wei. Research progress of anti-tumor mechanism of active ingredients of Astragalus membranaceus [J] . Chinese herbal medicine, 2022, 53 (23): 7613-7623

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Research Progress on anti-tumor mechanism of active ingredients of Astragalus membranaceus

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