Research,progress,on,the,mechanism,of,Zuojin,Pill,in,inhibiting,cancer

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Wei-Chen Si

1School of Acupuncture-Moxibustion and Tuina,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China.

Zuojin wan first appeared in the mind art of dan xi,and it is recorded in the original text: “Zuojin wan is for treating liver fire”–for the first time illustrates the Zuojin Pill.The author of the book is Jin Yuan Zhu Danxi said four people.The evodia rutaecarpa and the coptis chinensis in the prescription form the Zuojin Pill according to the ratio of 6:1,the main medicine in the prescription is coptis chinensis with cold nature,which can clear liver fire and purge stomach fire,and the other evodia rutaecarpa has a mild and warm nature,which can warm the liver and dispel cold,etc.Its prescription has obvious medication characteristics.Coptidis Rhizoma,which has a bitter and declining nature,is used together with Evodia rutaecarpa,which has the effects of soothing the liver,regulating qi,regulating the stomach and lowering the inverse.This recipe is mainly used to treat the syndrome of liver-fire invading stomach in traditional Chinese medicine.Previous modern studies have proved that Zuojin Pill has the functions of inhibiting gastrointestinal motility,antagonizing bacteria,inhibiting gastric acid secretion,relieving pain and inflammation,and preventing oral ulcer [1].In recent years,studies have shown that Zuojin Pill also has anti-tumor effect.Here is a summary of its specific mechanism.

Apoptosis is primarily mediated through mitochondrial-dependent pathways and death receptors (Fas et al.) to activate the Caspase cascade [2–5].The process of apoptosis is regulated by P53 protein,survivin protein,Bcl-2 and Caspase family proteins [6].Bcl-2 gene family plays an important role in the regulation of apoptosis.The ones in this family that inhibit apoptosis include Bcl-2 and Bcl-xL,etc.;Pro-apoptotic proteins include Bax and Bak.Pro-apoptotic family members can promote the opening of mitochondrial permeability transition channels and the increase of membrane permeability,so that substances such as CytochromeC in mitochondria enter the cell sap and form an apoptosis complex with Apaf-1 and Caspase-9,which leads to the initiation of Caspase cascade reaction,the activation of Caspase-3 and other substrates,and the production of cell apoptosis[7].Bax and Bak can finally activate Caspase-3 through the mitochondrial pathway mentioned above and act on PARP,etc.,to induce apoptosis.In the research by Qingfeng Tang et al [8].The expression levels of Bax and PARP proteins and the apoptosis rate of MKN45 cells were increased after Zuojin Pill applied to Hp-infected human gastric cancer cell MKN45,indicating that Zuojin Pill could induce the apoptosis of Hp-infected human gastric cancer cell MKN45 by up-regulating the expression of Bax and its substrate PARP.Xu Lina et al showed that Zuojin Pill could up-regulate the expression of Bax and Bak,down-regulate the expression of Bcl-2 and Bcl-xL,increase the activity of Caspase-3 and Caspase-9,and induce the apoptosis of human hepatoma cell SMMC-7721,human lung cancer cell A549 and human colon cancer cell HCT-116 [9].

The production of reactive oxygen species (ROS) damages the mitochondrial membrane of cells,causing the collapse of mitochondrial transmembrane potential,and leading to the release of relevant pro-apoptotic factors in mitochondria,such as CytochromeC,into the cytoplasm and binding to Apaf-1,activating Caspase-9,producing Caspase cascade reaction,and finally activating Caspase-3,etc,leading to apoptosis [10–11].Peng QX et al applied Zuojin Pill to human gastric cancer cell SGC-790l and found that it induced ROS production[12].The results of JC-1 experiment confirmed that Zuojin Pill caused the collapse of mitochondrial transmembrane potential of SGC-790l.The results also showed that the expression of Bax was up-regulated and the expression of Bcl-2 was down-regulated,the activities of Caspase-9 and Caspase-3 were increased,and the apoptosis rate was increased.It indicated that Zuojin Pill could induce mitochondrial transmembrane potential collapse,up-regulate Bax expression and down-regulate Bcl-2 expression by producing ROS,and induce apoptosis of SGC-790l human gastric cancer cells based on a mitochondrial dependent manner.

The regulation of cell proliferation is very complex,mainly involving the molecules that regulate the cell cycle (such as cyclin),growth factors and their receptors (such as EGF and EGFR),oncogenes (such as c-erbB) and tumor suppressor genes (such as P53),signaling pathway (PI3K/AKT/mTOR),and so on.AP-1 and NF-kB are important effector molecules that regulate cell proliferation.Located in the nucleus,activatorprotein1 (AP-1) participates in gene transcription.It is composed of two subunits,c-Jun and c-Fos.Through the combination of leucine zipper and DNA,activated AP-1 can regulate the expression of a variety of genes,participate in cell apoptosis,proliferation and other biological functions,and promote the occurrence and development of tumors.AP-1 can regulate cell cycle based on a variety of different signaling pathways.The human cyclin D1 regulatory sequence contains two AP-1 binding sites,where AP-1/c-Jun can bind to cyclin D1 and induce transcription of cyclin D1 gene.AP-1/c-Jun can also inhibit the expression and function of tumor suppressor genes P53 and P16,and promote the abnormal initiation of cell cycle to participate in tumor cell proliferation [13].NF-kB is one of the important nuclear transcription factors in cells.It is a transcription factor composed of two combination of RelA (P65),c-Rel,RelB,NF-kB1(P50) and NF-kB2(P52).The activated NF-kB can regulate the transcription of many genes,and is involved in blocking tumor cell apoptosis,promoting tumor proliferation and angiogenesis,and promoting tumor development and distant metastasis.NF-kB can regulate cell cycle based on different signaling pathways.Recognition of human cyclin D1 by NF-kB,the two NF-kB binding sites in the(cyclinD1) promoter region bind to cyclinD1 and up-regulate the expression of cyclinD1 gene;NF-kB can also antagonize the activity and function of tumor suppressor gene P53,thereby promoting the cell cycle from G1 to S phase and promoting the proliferation of tumor cells [14].Chao DC et al found that the water extract of Zuojin Pill could inhibit the proliferation of human hepatoma HepG2 cells by inhibiting the activities of AP-1 and NF-kB[15].

After c-myc is activated,it inhibits the transcription of cell cycle/growth inhibitory genes (gas1,p15,p21,p27,gadd34,gadd45,and gadd153) and leads to the proliferation of tumor cells through at least two mechanisms.One mechanism is that Myc-Max heterodimer is connected to Miz-1 and others through its c-mycC terminal domain,while Myc-Max heterodimer is connected to Inr region of promoter of growth inhibition gene to inhibit transcription of growth inhibition gene activated by Miz-1 and others.Another mechanism is that the central region of c-myc binds to transcription factor Sp1 and inhibits the transcriptional activity of Sp1 [16].Chou Shunting et al demonstrated through microarray analysis that recombinant human hepatoma cell HepG2/NF-kB/Luc was respectively intervened with Zuojin Pill and its components at TC50 for 48 h,and they found that c-myc might be a key molecule for Zuojin Pill and its components to play a role in inhibiting the proliferation of hepatoma cells [17].

Under the action of a variety of effector molecules and signaling pathways,invasion and metastasis are completed through multiple steps such as tumor cell adhesion movement,degradation of extracellular matrix and basement membrane,and generation of tumor blood vessels.Tumor cell invasion and metastasis are mainly affected by tumor metastasis genes (Bmi-1,etc.) and metastasis suppressor genes (nm23,etc.),tumor angiogenesis related factors(VEGF,etc.),extracellular matrix.

Qualitative degradation enzyme (MMP,etc.),cell adhesion molecule (CD44,etc.),tumor microenvironment (inflammatory microenvironment,etc.) [18].Tumor Wnt/β-catenin pathway and MMP-7 effector molecules are involved in tumor invasion and metastasis.The Wnt/β-catenin signaling pathway is mainly responsible for the aggregation of β-catenin into the nucleus to activate target genes.In the presence of Wnt signal stimulation,the Wnt protein secreted by cells combines with the receptor Fz(Frizzled)and LRP-5 and LRP-6 on the surface of cell membrane to activate intracellular Dsh (Dishevelled),while the activated Dsh causes the complex composed of Axin,GSK-3β,CK1,APC and others to dissolve and cannot degrade β-catenin.It causes β-catenin to accumulate in the cytoplasm and move into the nucleus,combine with transcription factor TCF or LEF,and activate the transcription expression of downstream target genes such as c-myc,cyclinDl,MMP-7,CD44,and Claudin-1 under the assistance of other factors,to participate in the occurrence and development of tumors [19].MMP-7,as an important member of MMPs family,has a wide range of substrates that can degrade a variety of extracellular matrix and basement membrane proteins,and activate other MMPs to promote tumor invasion and metastasis[20].Zhang Yanbo et al found that Zuojin Pill could reduce the activity of Wnt/β-catenin pathway and down-regulate the expression of target gene MMP-7 and ultimately inhibit the metastasis of human gastric cancer MKN45 cells by down-regulating the expression of β-catenin [21].

Multidrug resistance(MDR)of tumors refers to resistance not only to a drug in contact but also to other drugs that are structurally unrelated and have different mechanisms of action,which is one of the main causes of chemotherapy failure [22].The mechanism of MDR in tumors is complex,which mainly includes the effects of MDR-related proteins and enzymes,DNA damage and repair of tumor cells,abnormalities of apoptotic pathways,and autophagy [23].The most common mechanism of MDR in tumors is the overexpression of P-gp encoded by MDR1 gene.P-gp is an ATP-dependent output pump,which can export the antitumor drugs that have entered the cells out of the cells and reduce the concentration of intracellular drugs [24].PI3K/AKT/NF-kB pathway regulates the P-gp-mediated multi-drug resistance mechanism of tumors.Under the action of GPCRs,RTKs or mutated RAS,PI3K catalyzes the production of a second messenger PIP3.Akt binds to PIP3 through its PH domain.Akt is recruited to the cell membrane and activated.Activated Akt regulates the activity of IkB kinase (IKK),phosphorylates and ubiquitinates Ik B.The IkB is degraded and released,and NF-kB which combines with IkB to form an inactive complex in the cytoplasm is activated and enters the nucleus.The activated NF-kB activates the promoter of MDR1 gene,regulates the expression of MDR1 gene,and promotes the expression of P-gp encoded by MDR1 gene,leading to multi-drug resistance of tumor cells [25].Sui Hua et al found that Zuojin Pill could down-regulate the expressions of P-gp,p-AKT,p-IkB and NF-kB/p65 in human colon cancer multidrug-resistant cell HCT116/L-OHP,indicating that Zuojin Pill could reverse the multidrug resistance of human colon cancer multidrug-resistant cell HCT116/L-OHP and inhibit PI3K/AKT/NF-kB pathway[26].Further study found that after HCT116/L-OHP cells were treated with PI3K/AKT signal activator(IGF-1),Zuojin Pill was down-regulated.

The weakened expressions of P-gp,p-AKT,p-IkB,and NF-kB/p65 indicated that Zuojin Pill could reverse P-gp-mediated resistance of HCT116/L-OHP by inhibiting PI3K/AKT/NF-kβ pathway.Tang QF et al found that Zuojin Pill could induce the dephosphorylation of p-Colin -1,promote the transfer of Colin-1 (mitogen-1) into mitochondria,induce the conversion of polymorphonuclear actin into spherical actin,and calcium overload occurred,causing mitochondrial damage,thus triggering the apoptotic pathway of the mitochondrial pathway and inducing the apoptosis of human gastric cancer cells SGC7901/DDP and BGC823/DDP,if it acts on DDP-resistant human gastric cancer cells SGC7901/DDP and BGC823/DDP [27].

In summary,the research progress on the anti-tumor mechanism of Zuojin Pill is mainly as follows:Zuojin Pill exerts the anti-tumor effect by inducing apoptosis,inhibiting proliferation,inhibiting invasion and metastasis,and reversing MDR through multiple pathways and multiple targets.In recent years,the research subjects are mainly human gastric cancer,colon cancer,liver cancer and lung cancer.Cell experiments and animal experiments are the majority,while clinical research reports are few.Therefore,in future development,we need to reveal the anti-tumor effect and mechanism of Zuojin Pill from a clinical perspective,provide a scientific basis for the new use of ancient prescriptions,and further promote the application and promotion of Zuojin Pill in clinical treatment of tumors.

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