Advances in the study of the inhibitory effect of apigenin (chamomile extract) on tumor
Advances in the study of the inhibitory effect of apigenin (chamomile extract) on tumor
Malignant tumors are increasingly threatening to human health, and about 7 million people die from malignancies every day around the world. Malignant tumors are closely related to dietary patterns. Good eating habits and dietary patterns are one of the important measures to prevent malignant tumors. Some of the food factors associated with the prevention of tumorigenesis have been studied. Some have made great progress in theory, and are widely found in many fruits and vegetable flavonoids apigenin and tumor occurrence and development are closely related, has made some research results. In this paper, Apigenin in the anti-tumor aspects of the experimental and mechanism of the progress of the study was reviewed.
Experimental study on the effect of apigenin on tumor
1.1 Breast cancer
In vitro and in vivo experiments have shown that Apigenin can inhibit the malignant biological behavior of human breast cancer cell line ZR-75-30 and its nude mice from various aspects, from proliferation, invasion ability, angiogenesis and cell Apoptosis and other aspects of anti-breast cancer play a role, and shows more than TAM (tamoxifen) more significant results and lower toxic side effects. The latest study also suggests that apigenin may inhibit the expression of VEGF mRNA by reducing the transcriptional activity of the VEGF promoter, inhibiting the expression of VEGF mRNA, reducing the secretion of extracellular VEGF protein levels, and inhibiting the expression of VEGF in human breast cancer cells. Proliferation state irrelevant I “.
1.2 Gastric cancer
Apigenin can cause apoptosis of human gastric cancer cells. The apoptosis rates of Apigenin (2o, 40,80 g / mL) treated BGC823 cells were 13.1%, 20.6% and 34.0% respectively after 48h, 2.9% higher than the control group. It was suggested that apigenin could promote the apoptosis of BGC823 cells in a concentration-dependent manner. Apigenin Apoptosis induced BGC823 mainly by activating the mitochondrial pathway. Caspase-9 is the key caspase-induced apoptotic pathway in mitochondria, apigenin Apigenin increases in a dose-dependent manner cap. Se-9 activity, the caspase-9 inhibitor can significantly inhibit the role of API in enhancing caspase-9 activity. Further studies showed that the expression of Bax protein increased with the increase of apigenin concentration, the expression of bcl-2 protein decreased, the ratio of Bax / bcl-2 increased gradually, the release of Cyt c increased with the increase of apigenin concentration, 9 and caspase-3 protein expression also increased with the increase of API concentration. Caspase-9 inhibitor Ac-LEHD-CHO can block the above effects of the API .
1.3 Prostate cancer
It was found that apigenin could block cell cycle arrest in G # M phase and inhibit the growth of CA-HPV-1 prostate cancer cells in a dose-dependent manner. Apigenin apoptin was significantly induced by CA-HPV-10 cells in prostate cancer Apoptotic effect. Ephedrine also allows PC-3m cells to undergo GGG phase cell cycle arrest. High concentration was particularly significant, and 100 mol / L group induced a certain percentage (16.19%) of apoptosis. Apigenin can not only induce apoptosis directly but also improve the “bystander effect” of the HSV-TK / GCV regimen, thereby improving the efficacy of treatment of prostate cancer .
1.4 Liver cancer
Apigenin has the effect of inducing differentiation of human hepatoma cells (Hep G). A GT and TAT are markers of liver cancer, a GT and liver cancer differentiation were negatively correlated, while the latter was positively correlated. AFP in liver cancer cells are usually overexpressed, is an important marker of liver cancer. In addition, ALP is a marker of tumor cell differentiation. All-trans retinoic acid significantly increased ALP activity in BEL-7402 cells, indicating that ALP can also reflect the differentiation of hepatocellular carcinoma cells, which is one of the markers of differentiation of hepatocarcinoma cells. The results showed that 10 mol / L apigenin and all-trans retinoic acid could effectively decrease the activity of A and the expression of AFP and enhance the activity of TAT and ALP. These results further confirmed that apigenin and all-trans retinoic acid could effectively induce the differentiation of Hep G human hepatocellular carcinoma cells.
1.5 Ovarian cancer
Apigenin has an inhibitory effect on the proliferation of human ovarian cancer CAOV3 cells. Apigenin 20 ~ 160 mol / L has a significant inhibitory effect on the proliferation of CAOV3 cells, and it is time-dose-dependent. Apigenin blocking CAOV3 cell cycle in G2, I Ⅵ, so that cells can not enter the next cell cycle G period. Apigenin may inhibit the growth of CAOV3 cells by blocking the CAOV3 cells in the G phase, and then induce the cells to enter the program of death, which play a role in inhibiting the growth of CAOV3 cells ridicule.
Apigenin has the effect of inducing mouse skin cancer cells and human leukemia HL-60 cells to stop in the G phase, and this blockade is reversed after removal of apigenin 24 h apigenin.
Tumor research also found that apigenin on skin cancer, bladder cancer, melanoma, lung cancer, thyroid cancer, endometrial cancer, adrenal cortical cancer, neuroblastoma and other different tumor cells have inhibited.
Antitumor mechanism of apigenin apigenin
2.1 direct inhibition of tumor cell growth
Its mechanism of action mainly includes the following aspects.
2.1.1 induced apoptosis apigenin Apigenin by PI3K / AKT pathway to dissociate HER2 / neu protein, which induced HER2 / neu high expression of breast cancer cell apoptosis, cytochrome c release, caspase-3 activation, DFF-45 protein degradation, as well as cyclinDl, D3 and Cdk4 down-regulation and p27 up-regulation are involved in this cell apoptosis process. Apigenin can also induce human cervical cancer cells HeLa G. And the expression of p21 / WAF1, Fas / APO-1, and caspase-3 were increased, and the expression of Bcl-2 was decreased. In HepG2 cells, apigenin can induce apoptosis of HepG2 cells by activating TNF-alpha and IFN gamma-mediated caspases and p53-p21 / WAF1 pathway. Recent studies have shown that apigenin can inhibit tumor cell fatty acid synthase (FAs), Apigenin-induced apoptosis and its inhibition of adipogenesis is highly correlated.
2.1.2 inhibition of oncogene / induced tumor suppressor gene expression Apigenin can reduce c-Myc phosphorylation levels, reduce Rh protein phosphorylation, increase wild-type P53 stability and transactivation activity and improve wild-type P53 Protein content, P53 downstream effect factor P21 / WAFL protein level and inhibit the growth of tumor cells, apigenin Apigenin can also be induced by Bax gene expression and inhibition of Bcl-2 gene expression, change Bax / Bcl-2 ratio, Play a role in inducing tumor cell apoptosis
2.1.3 Interference of tumor cell signaling A large number of studies has shown that apigenin Apigenin has a strong inhibitory effect on protein kinases and inhibits cell signaling by inhibiting multiple protein kinases. Apigenin has a strong effect on interfering with tyrosine kinase and protein kinase, reducing the binding site for the response protein Grb2, thereby achieving the effect of inhibiting the MAPK cascade. At the same time, apigenin could induce the recovery of the phenotype of vH ras-transformed NIH 3T3 cell line at low concentration (12.5mm / L). By inhibiting the activity of MAPK, the apoptotic cells were blocked by G2 / M phase to inhibit its proliferation and promote morphological differentiation
2.1.4 Cell cycle arrest Apigenin by down-regulation of cyclin A, cyclin B expression, and reduce cdc2, cdc25 phosphorylation induced pancreatic cancer cell G2 / M phase arrest [ll]. Apigenin can up-regulate the expression of p21 / WAF1 through the non-p53-dependent pathway in HT-29 and MG63 cells containing the mutant p53 gene, thus inducing cell arrest in G phase. Apigenin can increase the expression of WAF1 / p21, KIP1 / p27, INK4a / p16 and INK4c / p18 in the tumor tissue of nude mice transplanted in prostate cancer, and the expression of cyclins D1, D2, E and CDK, cdk2, cdk4 and cdk6 decreased, Reduce the phosphorylation of serine780 of Rb and stabilize the phosphorylation of p53 serine15, so apigenin in vivo can also inhibit tumor growth and induce apoptosis by cell cycle regulation fI2]
2.1.5 promote cancer cell differentiation apigenin Apigenin can promote HL-60 cells to mononuclear cell differentiation. Apigenin also has the effect of inducing differentiation of human hepatoma cells (Hep G2).
2.2 inhibit tumor growth, invasion, and metastasis
It is known that HIF-1alpha and VEGF are angiogenic factors. Recent studies have shown that Apigenin can inhibit the expression of HIF-1alpha in lung cancer cell A549 in vitro, thereby inhibiting the transcriptional activation of VEGF, and further in vivo studies have found that HIF in nude mice tumor tissue. 1 a1pha and VEGF expression were reduced (iv). In ovarian cancer cells, apigenin down-regulates the expression of HIF-1Mpha and VEGF through the PI3K / AKT / p7OS6K1 and HDM2 / p53 pathways. In vitro studies have shown that Apigenin, an apigenin, can partially reduce the expression of urokinase plasminogen activator in breast cancer cells and completely inhibit the secretion of matrix metalloproteinase-9 and thus inhibit the invasion and metastasis of tumor cells Effect l_
2.3 Antioxidant effects of apigenin apigenin
Apigenin is one of the anti-cancer mechanisms by preventing the occurrence of a tumor by anti-oxidation. Apigenin can reduce the production of oxygen free radicals, scavenge free radicals, inhibit lipid peroxidation and play an antioxidant effect, the study found that apigenin Apigenin can prevent N-nitrosamine (DEN) induced liver cancer rates In vivo lipid peroxidation (Lipid peroxidation, LPO), the protection of rat antioxidant system.
2.4 chemical prophylaxis of tumors
Apigenin was able to compete with ATP for binding to PKC, significantly reduced the activity of PKC in the cells, and the activity of tyrosine protein kinase TPK was decreased after treatment with apigenin, which attenuated the intracellular protein C-foes and c-junk genes were also significantly inhibited. The expression of c-foes and c-junk proteins of c-foes and c-junk genes belonged to transcription factors and could regulate mRNA at the transcriptional level. Protein synthesis, which is closely related to cell growth and differentiation, in which c-junk mediates tumor progression. Apigenin can also significantly inhibit DMBA as an initiator, TPA as a carcinogen-induced SENCAR mouse skin cancer, apigenin Apigenin this role and apigenin Apigenin can reduce TPA activated epidermal cell ODC activity.
Recent studies have found that Apigenin can upregulate the expression of WAF1 / p21 in human lung cancer cells and down-regulate the expression of Bcl-2 in lung cancer cells, thereby increasing the sensitivity of tumor cells to radiotherapy and promoting apoptosis. Apigenin derivatives also increase the sensitivity of MRP1-mediated MDR cells to doxorubicin. Apigenin reduces ATP production by inhibiting ATPase activity, reducing the energy supply of MRP1 to transport chemotherapeutic drugs into cells, inhibiting the extracellular effusion of tumor cells, that is, increasing the concentration of intracellular chemotherapeutic drugs, Cell multidrug resistance.
In conclusion, as a natural flavonoid compound, apigenin Apigenin inhibits the malignant biological behavior of tumor cells in recent years. Apigenin can inhibit tumor cell growth, invasion and induce angiogenesis through a variety of mechanisms, and induce apoptosis of tumor cells. However, the present study focused on the role of Apigenin in the preclinical model of cancer. Further research is necessary. It should be necessary to increase the clinical preclinical model of an animal, which is closely related to human tumor and can carry out a large number of clinical trials. Does Apigenin also have biological and pharmacological effects consistent with it’s in vitro or in vivo tumor cells and their safety and side effects on human use?
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