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Antitumour Activity and Action Mechanism of Escin

Author: ZhouXueYing
Tutor: WangChangHai
School: Dalian University of Technology
Course: Biochemical Engineering
Keywords: Sodium aescinate Anti-tumor activity Cell Cycle Apoptosis Caspase -independent
CLC: R285.5
Type: PhD thesis
Year: 2009
Downloads: 405
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Abstract

Aescin pentacyclic triterpenoid saponins, is a non-steroidal anti-inflammatory drugs, its the sodium salt aescine sodium widely used in clinical, anti-exudative and increase venous tone, swelling, anti-inflammatory and improves blood circulation effect. In recent years, non-steroidal anti-inflammatory drugs, anti-tumor effect of concern, but less anti-tumor activity of the sodium aescinate research. Cancer cells and tumor-bearing Kunming white mouse model, in vitro and in vivo anti-tumor activity of sodium aescinate conduct a study on the synergy of its role and relationship of time and dose when used in combination with chemotherapy drugs, its anti-tumor mechanism of action and the use of methods such as cell biology, biochemistry and molecular biology research, and provide a theoretical basis for sodium aescinate in the clinical application of cancer treatment. The point of this study are as follows: 1, the proliferation of human cancer cells, inhibition effects of aescin in the human hepatoma cell line SMMC7721 and HepG2, human cervical carcinoma cell line HeLa, human lung adenocarcinoma cell line A549, early promyelocytic acute leukemia cell line HL-60 human laryngeal squamous cell carcinoma Hep-2, human gastric cancer cell SGC-7901 and BGC-823 proliferation. The results show that, the Sodium Aescinate can significantly inhibit tumor cell growth, the IC ₅₀ distribution between 37.33 ~ 50.24μg/mL, and this inhibition in a dose-and time-dependent; When the sodium aescinate in combination with cisplatin, doxorubicin, and mitomycin, significantly enhanced the proliferation of SMMC-7721 and HepG, of which the most significant synergistic effect of low concentrations of chemotherapy drugs. 2, the tumor-bearing Kunming white mouse tumor suppressor effect in solid tumor model, intraperitoneal injection of 2.8 mg / kg and 1.4 mg / kg doses of the sodium aescinate on H22, S180 sarcoma and U _{14 have a significant inhibitory effect on the growth of cervical cancer}; ascites tumor model, in addition to the 0.7 mg / kg dose group was not statistically significant role of S180 ascites carcinoma, the rest of the treatment group of three kinds of ascites tumor growth has a strong inhibitory effect, can significantly prolong the survival of ascites tumor in mice. When 1.4 mg / kg and 2.8mg/kg aescine, sodium and 2 mg / kg doxorubicin when used in combination, the H22 solid tumor inhibition rate were as high as 47.9% and 55.3%, with H22 ascites tumor in mice life span, respectively, 50.0% and 54.2%, respectively, in the two tumor models drug interactions are synergistic; sodium aescinate of 0.7 mg / kg and 2 mg / kg doxorubicin, solid tumor inhibitory rate of 27.7%, and extend the life of the Dutch ascites tumor-bearing mice was 33.3%, drug interactions are additive. The sodium aescinate no significant effect on tumor-bearing mice immune parameters, not improve immunity to anti-tumor effect. 3, anti-tumor mechanism of action (1) cell cycle arrest. The sodium aescinate can HepG2 cell cycle G ₁ / S phase arrest in a dose-dependent manner, and the regulation of the cell cycle. Sodium aescin by downregulating Cyclins E, Cdk2 expression, so that the concentration of the cells within CyclinE CDK2 composite material decreases, thereby hindering the Rb protein phosphorylation induced dephosphorylation of Rb protein levels increased and in a corresponding decrease of the level of pRb. Dephosphorylation of Rb protein and E2F protein binding, reducing the level of intracellular free E2F, the E2F activation of S phase gene expression reduced ability, resulting in a large number of cell cycle arrest at the G ₁ period. (2) induction of apoptosis. Aescin sodium can induce HepG2 the cells PARP-1/AIF mediated Caspase-independent apoptosis, leading to chromatin condensation and DNA breakage of approximately 50 kb fragment. PARF-aescin sodium in the treated cells do not rupture, but rather to maintain the activity of to impact mitochondrial membrane permeability, resulting in HepG2 cells AIF, Cyt C release from mitochondria to the cytoplasm to the nucleus sub, Bax/Bcl-2 expression ratio increased to promote the release of Cyt C. The AIF direct role in the nucleus, chromatin damage and produce about 50 kb DNA fragment. The process is not accompanied by caspase activation, to prove sodium aescinate Caspase-independent way to induce apoptosis in HepG2 cells. (3) synergistic effect of lower concentrations of chemotherapeutic drugs. Of 5μg/mL or 10μg/mL aescine sodium a lower concentrations of cisplatin, doxorubicin and mitomycin combined effects of tumor cells, sodium aescinate of the membrane permeability, and promotes more chemotherapy drugs molecules through the cell membrane into the cell, in order to achieve the synergistic effect of anti-tumor activity of lower concentrations of chemotherapeutic drugs.

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