Anti-tumor mechanism of Angelica and its compound preparations

Xin-Xiao Lu Xiong-Zhi Wu *

1 Tianjin Medical University Cancer Institute and Hospital, Tianjin 300070, China.

Abstract

Keywords:Angelica, Compound preparations, The anti-tumor effect

Introduction

With the changes in modern living habits and environmental changes, the incidence of malignant tumors in China has increased year by has become a threat to national health [1].At present, although the radiation therapy and chemotherapy of tumors in clinical practice are valid, they all have severe toxic and side effects such as inhibiting the body's immune function, making it difficult for patients to adhere to treatment.Chinese medical researchers have discovered through clinical and basic experimental research over the years that Chinese medicine combined with chemotherapy drugs can reduce the side effects of chemotherapy drugs to a certain extent in the treatment of tumor medicine.Besides, it can significantly improve cancer drug treatment sensitivity [1].AngelicaSinensisis the dry root ofAngelicaSinensis(Oliv.) Diels, which has the functions of improving immunity, anti-oxidation,scavenging free radicals, anti-radiation damage, and anti-tumor, which has a broad clinical application [2].Angelicais a holy medicine for gynecology, clinically used for blood deficiency and chlorosis, dizziness and palpitation, irregular menstruation, dysmenorrhea,abdominal pain, rheumatism, hemorrhoids, constipation.In recent years, with the discovery of polysaccharides enhancing the immune function and anti-tumor effects of the body,Angelicahas attracted more and more attention from researchers at home and abroad [3].This article reviews the anti-tumor mechanism ofAngelica,and it's compound preparations，to provide a theoretical basis for the patient's clinical treatment medication, to ensure the patient's clinical efficacy and medication safety.In the world and has the third highest cancer mortality rate in China [8].Treatment of hepatocellular carcinoma (HCC) has been developed from surgery and radiotherapy over interventional chemoembolization to new molecular targeted drugs [9-10].In recent years,based on Chinese medicine, which has been widely used in comprehensive clinical antitumor treatment,domestic and foreign scholars have been exploring a new path of hepatocellular carcinoma treatment.

Angelica and its ingredients

Solid tumors have a higher degree of malignancy.When solid tumors are first described clinically, most have entered the middle and late stages.They are prone to recurrence and metastasis, and the treatment efficacy is weak.Some studies have found that patients with solid tumors are hypercoagulable, and hypercoagulability is one of the important conditions for tumor recurrence and metastasis.Liuet al.[4] included 80 patients with Qi stagnation and Blood stasis syndrome to study the effect ofAngelicaon blood rheology in patients with Qi stagnation and Blood stasis [5].The experimental results showed that the clinical efficacy and improvement of hemorheology index were significantly better in the observation group (the regular chemotherapy regimen givenAngelica15g/d) than the control group (giving regular regimen chemotherapy),and did not increase adverse reactions [6].It is suggested thatAngelicacan improve the hypercoagulable state and microcirculation disorder of solid tumor patients, thereby enhancing the inhibition of chemotherapy drugs and killing tumors [7].

The chemical constituents ofAngelicamainly include volatile oils and water-soluble fractions.The volatile oil mainly contains more than 40 components such as nonylphenyl lactone andAngelicaketone; the water-soluble part mainly contains ferulic acid,Angelicapolysaccharide, amino acid,et al.In addition,it also contains trace elements such as calcium, sodium,copper, iron, manganese, and zinc, as well as uracil,adenine, and vitamin E.Studies have shown that the central effective part with ascending blood ofAngelica Sinensisis theAngelicapolysaccharide, and the active part with activating blood is mainly volatile oil and ferulic acid.

Angelica oil

The volatile oil is an important component ofAngelica,with a content of about 0.4%, including neutral oil,phenolic oil, and acid oil.Zhuet al.[8] research the effects ofAngelicaoil on the proliferation of human prostate cancer PC3 cells, human breast cancer MDA-MB-435 cells and human cervical cancer HeLa cells in vitro.Results show thatAngelicaoil inhibits the growth and proliferation of prostate cancer PC3 cells,cervical cancer HeLa cells, and breast cancer MDA-MB-435 cells, and can achieve an inhibition rate of more than 60% at a lower concentration.

Benzoquinone

Chenet al.conducted a cytotoxic activity study on the new benzoquinone dimers neodiligustilide and Z-ligustilide isolated fromAngelicaSinensis.It was found that Z-decalactone significantly inhibited the proliferation of L1210 and K562 tumor cells, and their IC50 were (2.27 ± 0.10) and (4.78 ± 0.18) μmol·L-1,respectively.However, Neodiligustilide has a moderate inhibitory effect on these two tumor cells, and its IC50 is (5.45 ± 0.19) and (9.87 ± 0.14) μmol·L-1,respectively.

Angelica polysaccharide

Angelicapolysaccharide (APS) is one of the important components of traditional Chinese medicineAngelica Sinensis.Polysaccharides have a variety of pharmacological effects, as anti-tumor drugs, are biological reaction modulator (BR) anti-tumor drugs[9].

Chenget al.[10] studied the effect ofAngelica Sinensispolysaccharide on tumor growth by establishing the H22 tumor-bearing mouse model.The experimental results showed that the low, medium, and high doses ofAngelicaSinensispolysaccharide had a specific anti-tumor effect and significant inhibition of the expression of hepcidin and IL-6 [11].The concentration of hepcidin in the serum of H22 tumor-bearing mice was significantly higher than that in normal mice.After administration of ASP, the content of hepcidin in the low, middle, and high dose groups were significantly decreased.The serum IL-6 concentration in H22 tumor-bearing mice was significantly higher than normal.In mice, IL-6 levels were significantly reduced after administration of ASP.During tumor growth, hepcidin plays a role in regulating iron metabolism in innate immunity, but it also hinders the body's uptake and utilization of iron,which may be the primary mechanism for long-term infection and causing chronic anemia and even iron deficiency anemia.Therefore, the anti-tumor effect ofAngelicapolysaccharide in vivo may be related to the regulation of iron metabolism.

Angelica Polysaccharide AP-0

Shanget al.[9] used mouse sarcoma S180, ascites type tumor Ehrlich ascitic cancer (EAC) and mouse leukemia L1210 three different types of transplanted tumor models, observedAngelicapolysaccharide AP-0 to the inhibition of tumors.The results showed that AP-0 had a well inhibitory effect on transplanted ascites-type tumors EAC and L1210, which could significantly inhibit the production of ascites and prolong the survival time of tumor-bearing mice.For the solid tumor S180, although there is no apparent anti-tumor effect, it can cause noticeable atrophy of the immune organ-thymus of the tumor-bearing mice,suggesting that AP-0 can affect the function of the immune system.

Angelica polysaccharide-1cII

AngelicaSinensis-1cII (APS-1cII) is a homogeneous polysaccharide with a relative molecular mass of 3.9*104 linked by a 1, 4-glucose residue and a 1,6-glucose residue.Cao Weiet al.[12] used in vitro cultured tumor cells to determine the cytotoxic effect of APS-1cII on tumor cells, and used mouse tumor model to observe the inhibitory effect of APS-1cII on transplanted tumors, and preliminary study the immune mechanism against tumor effects.The results showed that APS-1cII had no apparent inhibition of tumor cell proliferation in vitro, but the in vivo experiment had a visible anti-tumor effect on S180 tumor-bearing mice.In the experiment, the quality of life of the tumor-bearing mice in the APS-1cII group was significantly higher than that in the negative control group.The tumors were small, the animal reaction and activity were relatively agile, and there was no obvious dyspraxia at the end of the experiment.Moreover,APS-1cII can significantly increase the spleen index,thymus index, and lymphocyte count of tumor-bearing mice.These results suggest that APS-1cII has anti-tumor and certain immunomodulatory effects with less toxic side effects.This experiment found that APS-1cII can significantly enhance the phagocytic function of macrophages and stimulate the secretion of TNF-α and IL-1β by mouse macrophages, which may be one of the important mechanisms for its anti-tumor effect [13].

Angelica polysaccharide-2a

AngelicaSinensispolysaccharide was separated and purified by anion exchange cellulose column and gel column chromatography to obtain white flocculent polysaccharideAngelicapolysaccharide-2a (APS-2a).APS-2a was a homogeneous component with a weight average molecular weight of 7.4*105Da.It is composed of arabinose-galactose-rhamnose-glucose-galacturonic acid (38.2:7.5:2.6:1.0:4.9) and is the first novel acidic polysaccharide isolated fromAngelica.Caoet al.[14]experimentally studied the inhibitory effect of APS-2a on mouse S-180 sarcoma and compared APS-2a with cyclophosphamide.The results showed that the inhibition rate of APS-2a was negatively correlated with dose.The low dose ofAngelicaSinensispolysaccharide APS-2a increased the spleen index and thymus index of tumor-bearing mice.The spleen index and thymus index of three doses of APS-2a were significantly increased compared with cyclophosphamide group.These results suggest thatAngelicaSinensispolysaccharide APS-2a has an anti-tumor effect and has a specific immunomodulatory effect [15].

Angelica Polysaccharide-bII

The crude polysaccharide was extracted fromAngelica Sinensisand purified by anion exchange cellulose column and gel column chromatography to obtain white powdery polysaccharide,AngelicaSinensispolysaccharide-bII (APS-bII).APS-bII was a homogeneous component with a molecular weight of 13KDa.It is composed of glucose-galactose-xylose-arabinose (8.4:2.7:1.8:1.0)and is the first heteropolysaccharide isolated fromAngelica.Chen [16] used AMD-blue colorimetric assay to observe the growth inhibitory effect of APS-bII on various tumor cells.The results showed that APS-bII in the concentration range of (3-1000) mg.L-1 inhibited the proliferation of human cervical cancer cell line HeLa, human hepatoma cell line HepG2, human breast cancer cell line MCF-7, and human colon cancer cell line SW1116 in a dose-dependent manner.However, the anti-tumor mechanism of APS-bII remains to be further studied.

Angelica Polysaccharide-3c

Chinese crudeAngelicaSinensispolysaccharide was separated and purified by anion exchange cellulose column and gel column chromatography to obtain pale yellow powdery polysaccharideAngelicapolysaccharide-3c (APS-3c).APS-3c is a homogeneous component with a molecular weight of 1.4*104 Da by arabinose-rhamnose-glucose-galactose-mannose-xylose-galacturonic acid (6.7:6.5:6.3:4.7:1.6:1.0: 13.2)Composition.Caoet al.[17] observed the inhibitory effect of APS-3c on the growth of various tumor cells by using tetramethylazozolium blue colorimetric method.The results showed that APS-3c has a certain inhibitory effect on some tumor cells such as human myeloid leukemia HL-60 cells and human colon cancer SW1116 cells.The anti-tumor mechanism of APS-3c needs to be further studied [18].

Ferulic acid

Ferulic acid (FA) Chemical name is 4-hydroxy-3-methoxybenzene acrylic acid, a plant-derived phenolic acid.It is one of the main monomeric active ingredients in water-soluble extracts of Chinese herbal medicines such asAngelica, Awei,and Chuanxiong.In recent years, studies have found that ferulic acid has a significant anti-tumor effect.Liuet al.showed that ferulic acid inhibited the proliferation of human colorectal cancer Moser cells and breast cancer MCF-7 cells in a dose-dependent manner.Its growth inhibition effect on Moser may be achieved by inducing apoptosis.

Angelica compound preparations

Angelica Fritillaria Sophora Pills

AngelicaFritillaria Sophora Pills were initially used to treat women with urinary dysuria.Angelicais good medicine for blood supplementation.It is longer than nourishing blood and moistening dryness, and it can promote blood circulation and dissipate blood stasis,Sophora heats, dampness heat.The combination of various medicines, which constitutes a combination of cancer, can be used to treat genitourinary tumors [19].She [19] found that theAngelicaSinensisSophora Pill can not only enhance the inhibitory effect of cisplatin on H22 tumor-bearing mice but also reduce the cisplatin chemotherapy burden to H22 tumor, have specific synergistic and attenuating effects, which provides a pathological basis for the clinical application ofAngelicaFritillaria Sophora pills to assist cisplatin chemotherapy [20-21].

Angelica Fritillaria Sophora Pill Flavoring sides

AngelicaFritillaria Sophora Pills flavorAngelicaFritillaria Sophora Pill Flavoring sides and the whole group ofAngelicaFritillaria Sophora Pill Flavoring sides is accurately selected for the pathogenesis of liver cancer.The overall effect of the composition is to promote blood circulation, detoxification, and attack cancer, and to take into account the regulation of the body tonic and righteousness, and the function of blood stasis.Liu [22] showed that theAngelicaFritillaria Sophora Pill Flavoring sides could reduce the tumor tissue and significantly inhibit the growth of the tumor,and the anti-tumor effect is more evident after combined with chemotherapy drugs [23].Immunohistochemical studies showed thatAngelicaFritillaria Sophora Pill Flavoring sides could inhibit the expression of MMP13 and bFGF mRNA and protein in tumor tissues, and the expression of MMP13 and bFGF mRNA and protein is more obvious reduce combined with chemotherapy drugs [24-25].Fan [26] showed that the addition ofAngelicaFritillaria Sophora Pill Flavoring sides has a significant anti-tumor effect on MFC gastric cancer-bearing mice, and can down-regulate the expression of TLR2, TLR4, TLR6 and My D88 mRNA and protein in tumor-bearing mice.

Danggui Buxue Tang

Danggui Buxue Tang is composed ofAstragalus MembranaceusandAngelicain a ratio of 5:1, which are the representatives of promoting blood circulation[27].In recent years, it has been confirmed by a large number of clinical and animal experiments that the Chinese herbal medicines ofAngelicaSinensisandAstragalus Membranaceushave the functions of promoting cell regrowth and protecting organs, which can significantly reduce the damage of chemotherapy and side effects to the body [28].It has been shown that Danggui Buxue decoction is effective for chemotherapy attenuating synergist [29].

Sun [30] shows the prevention and early application of Danggui Buxue Tang alone has a certain effect through the establishment of tumor-bearing mice (EL-4 tumor strain) model.Chen Yuting [31] showed that the combination of Danggui Buxue Tang and chemotherapeutic drug cyclophosphamide could enhance the effect of cyclophosphamide on inhibiting tumor growth, and at the same time reduce the damage caused by bone marrow suppression, immune function and liver function, suggesting that Danggui Buxue Tang has synergistic and attenuating effects in the treatment of tumors.Chen [32] randomly divided 80 patients with tumor postoperative into the observation group and the control group.The observation group was given the oral administration of Danggui Buxue Tang at the same time of chemotherapy, and the control group received chemotherapy plus oral leucoxene.The results showed that IgG and IgM were significantly increased in the observation group, CD8 was significantly decreased,and CD4 / CD8 ratio was increased, indicating that the patient was often in an immunosuppressed state during postoperative chemotherapy, and the adjuvant cells of Danggui Buxue Tang could enhance the body immune function.

Myelosuppression is a common adverse reaction symptom in the chemotherapy treatment of malignant tumors, which can lead to the reduction of white blood cells in the blood of patients, resulting in decreased immunity and affecting patients' chemotherapy and quality of life.The study found that Danggui Buxue Decoction can not only improve the hematopoietic microenvironment, promote the proliferation of bone marrow cells, but also promote the proliferation of bone marrow hematopoietic stem cells and inhibit their apoptosis [33-34].Li [35] used 50 patients with malignant tumors as subjects and randomly divided them into experimental group and control group.The control group was treated with conventional chemotherapy, while patients in the experimental group are given Danggui Buxue decoction by conventional chemotherapy.The experimental results show that the treatment of tumor chemotherapy patients with Danggui Buxue decoction not only effectively improve the clinical symptoms and quality of life of patients but also effectively increase the number of white blood cells,platelets and hemoglobin in patients, thereby effectively alleviating the degree of myelosuppression to improve the quality of life of patients.Jiang [36] also showed that Danggui Buxue decoction not only has specific advantages in improving the clinical symptoms of patients with tumor chemotherapy and bone marrow suppression but also can increase the content of leukocytes, hemoglobin, and platelets in peripheral blood, thereby reducing the degree of bone marrow suppression in patients, improve the quality of life of patients.

Angelica anti-cancer mixture

Angelicaanti-cancer mixture is made up of 3 parts of Danggui Buxue Tang: 1 part of zedoaries.Danggui Buxue decoction can improve the body's immune function, improve their anti-tumor ability, and the zedoary is a kind of traditional Chinese medicine with elimination and analgesic effect, has a clear anti-tumor effect.Fan [37] showed that the anti-tumor rate ofAngelicaanti-cancer mixture was significantly higher than that of Danggui Buxue decoction and zedoaries group, and could significantly increase the spleen and thymus index of tumor-bearing mice;Angelicaanti-cancer mixture can enhance the killing ability of NK/M cells in tumor-bearing mice, and its enhancement is higher than that of Danggui Buxue decoction and zedoaries Group alone;Angelicaanti-cancer mixture can also induce the production of γ-IFN and reduce the level of TNF-α in tumor-bearing mice.The above results suggest that the compatibility ofAngelica Sinensisand zedoaries can significantly improve the tumor inhibition ability of each unilateral.

Danggui Huoxue decoction No.1

Yang [38] used Danggui Huoxue Tang No.1 in combination with chemotherapy in the treatment of 37 patients with advanced malignant tumors and compared with 37 patients with chemotherapy alone in the same period.The results showed that Danggui Huoxue Tang No.1 combined with chemotherapy could reduce bone marrow suppression in patients with chemotherapy,improving the patient's immune status and Karsten score, is conducive to the body's health, thus achieving the purpose of prolonging survival and improving quality of life.

Huang Yaozi is compatible with Angelica

P-gp is an ATP-dependent transmembrane transporter with a molecular weight of 170 kDa.It is an expression product of the multidrug resistance (MDR) gene, and it can excrete substances that are potentially toxic to cells,and P-gp overexpression is the main cause of drug resistance in tumor cells.Su Qing [39] shows thatAngelicacan increase the inhibition rate of Huang Yaozi on cancer cells and decrease the expression of P-gp.Therefore, the compatibility of Huang Yaozi andAngelicacan increase the anti-tumor effect by decreasing the expression of P-gp.

Conclusion

The above review shows thatAngelicahas an exact anti-tumor effect, andAngelicais highly effective and low-toxic compared to chemotherapeutic drugs.At present, the anti-tumor research ofAngelicahas made some progress, but it is necessary to recognize that the deep research institutes on the mechanism of its action are small and the research level is not deep.As the research progresses, more pharmacological effects are discovered, and the mechanism of its pharmacological effects will eventually be elucidated.