Anti tumor effect and mechanism of non steroidal anti-inflammatory drugs

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NSAIDs has been used in clinical practice for first years since the introduction of the (nonsteroid anti-inflammatory drugs, NSAIDs) aspirin

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NSAIDs has been used in clinical practice for first years since the introduction of the (nonsteroid anti-inflammatory drugs, NSAIDs) aspirin. It is mainly through the blockade of prostaglandin (PGs) synthesis mechanism to achieve anti-inflammatory, antipyretic and analgesic effects. In recent years, the research focuses on the anti-tumor effect and mechanism of NSAIDs, and has made some progress. Studies have shown that regular use of aspirin or other NSAIDs colon cancer incidence was significantly lower. NSAIDs can inhibit tumor by various mechanisms, and can act on multiple targets. Cyclooxygenase -2 (COX-2) is one of them, and the expression of COX-2 was found in the tissues of patients with ovarian cancer, prostate cancer and breast cancer, but no COX-2 expression was found in normal tissues. At present, it is believed that the anti-tumor effect of NASIDs is reflected in all aspects of the process of tumorigenesis, such as inhibition of COX-2 activity through multiple signaling pathways, inhibition of tumor angiogenesis, and promotion of tumor cell apoptosis. In recent years, the research progress of anti-tumor effect and mechanism of NSAIDs is reported as follows.

Antitumor effect of 1 NSAIDs

A lot of research reports showed that the inhibitory effect of salicylic acid, pyrazole ketones and acetic acid etc. different types of NSAIDs on different tumor has a certain degree of in vivo and in vitro and in clinical. Huang Yanjing, the study found that aspirin can proliferation of H4 human glioma cells in time dose dependently inhibited the in vitro expression, its mechanism may be related to induction of apoptosis, prolong the G0/G1 phase of the cell cycle, up regulation of p21 and p27 protein. The effects of NSAIDs on gastric cancer cell line SGC7901 and rectal cancer cells were inhibited in vitro. Johnsen study found that celecoxib can inhibit human neuroblastoma cell growth in tumor bearing mice in vivo. Sadeghi and other clinical analysis showed that conventional dose of aspirin can significantly reduce the incidence of breast cancer patients with hormone receptor positive. In recent years, the anti-tumor mechanism of NSAIDs has also been reported. Zhao Xiulan and other studies have found that NSAIDs can inhibit the activity of NF- kappa B by up regulating the expression level of RKIP, and promote the apoptosis of colorectal cancer cells in two. For the first time found Zhao Xianqi and so on, the expression of COX-2 in HCC cells of CBRH7919 rats; the effect of celecoxib on the growth of CBRH7919 cells with obvious inhibitory effect. Xu Dongkui and Cai Jianchun found that COX-2 was highly expressed in HCC cells. COX-2 is closely related to tumor, and has the function of tumor cell cycle arrest and tumor angiogenesis. NSAIDs can be through a variety of mechanisms against cancer, study on the static AEON and found that aspirin can inhibit the Wnt signal transduction pathway and inhibition of NF- kappa B activation and inhibition of NO synthase, cyclooxygenase and other regulatory mechanisms play a combined anti-tumor effect.

2 COX-2

COX-2 is the main target of anti-tumor effect of NSAIDs. COX is an important rate limiting enzyme in PGs synthesis, and there are at least two isozymes of COX-1 and COX-2. COX-1 is a kind of structural enzyme that plays a role in protecting mucosal cells. COX-2 is an inducible enzyme, which is expressed in many tissues. Recent studies show that COX-2 PGs catalyzed addition mediated inflammation, pain etc., also with some tumors especially closely related to digestive tract tumors. Wang Lifeng found that, compared with normal people, in 6% invasive squamous cell carcinoma and 70% esophageal adenocarcinoma patients with esophageal mucosa epithelium and esophageal tissue were detected in the high expression of COX-2 protein, indicating that COX-2 expression may be one of the reasons for the formation of esophageal adenocarcinoma. Stoppoloni et al. Found that COX-2 enhanced the digestion of basement membrane collagen matrix by activating the expression of -1 (MMP-1) and MMP-2, and enhanced the invasiveness of the tumor. This further shows that the expression of COX-2 plays an important role in tumor formation and growth.

3 antitumor mechanism of NSAIDs

3.1COX-2 is the main target of anti-tumor effect of NSAIDs. The anti-tumor mechanism of NSAIDs is mainly related to the inhibition of COX-2 expression. The results showed that the inhibitory effect of NSAIDs on gastric cancer was mainly related to the inhibition of COX-2 expression by. The relative expression of Kolev was detected by RT-PCR COX-2 mRNA the amount of experiments showed that the relative expression and lymph node metastasis of gastric cancer patients with COX-2 mRNA was significantly higher than that in patients without lymph node metastasis, and was proportional to the expression of lesion size and COX-2 in gastric carcinoma. Sheng research shows that the simultaneous injection of HCA-7 cells (the expression of COX-2 and mRNA (HCT-116) and the expression of COX-2 protein and mRNA) in nude mice model of colon cancer cell lines, injection of COX-2 inhibitor SC-58125 in 7d model mice, HCA-7 mice tumor inhibition rate was 90%, while the HCT-116 mouse tumor cell clones no effect. Xu Gang found that, combined with injection of COX-2 Inhibitor Celecoxib and gemcitabine in pancreatic cancer nude mice compared with gemcitabine alone group, was statistically significant differences in tumor inhibition. These observations suggest that COX-2 is a major target for the antitumor effect of NSAIDs.

At the same time, in the COX-2 dependent pathway, further mechanism of NSAIDs anti-tumor effect may inhibit angiogenesis through inhibiting the expression of COX-2, blocking tumor cell transfer. Wang Xiaomin found that celecoxib can was time dependent and dose dependently inhibited the in vitro expression of COX-2 protein in human cervical cancer HeLa cells, and then inhibit the proliferation of HeLa cells. Gore et al. Found that COX-2 could promote tumor angiogenesis. Therefore, by inhibiting the expression of COX-2, thereby inhibiting the formation of tumor angiogenesis can play an anti-tumor effect.

3.2 angiogenesis plays an important role in the formation and development of anti tumor by inhibiting angiogenesis. In addition, the formation of new blood vessels also play a positive role in the metastasis of tumor cells. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are the two most important factors in angiogenesis. They stimulate the secretion of endothelial cells by degrading the matrix components of the cell, forming a blood vessel in the interstitium. Shtivelband and other studies have shown that NSAIDs can inhibit the transcription of VEGF in the process of mRNA to inhibit the formation of colon cancer, thereby inhibiting colon cancer. PGs can stimulate the regeneration of capillary and promote the expression of VEGF, bEGF, and the expression of COX-2 was inhibited after PGs formation is inhibited, thereby affecting the expression of VEGF and bEGF, thus inhibiting the tumor angiogenesis, and inhibit the growth of tumor cells.

3.3 by inducing the apoptosis of tumor cells NSAIDs in addition to inhibiting the expression of COX-2 to play an anti-tumor effect, other NSAIDs, such as acid can be induced by tumor cell apoptosis to play a role. And the apoptosis of tumor cells induced by them may be related to the apoptosis related proteins Bcl-2, Bax and the inhibition of apoptosis protein peroxisome proliferator activated receptor delta (PPAR Delta). Gillissen study shows that the deletion of Bax gene in epithelial cells, NSAIDs can't make it happen apoptosis, and fluorouracil (5-Fu) can make the cell apoptosis, NSAIDs cell apoptosis induced by Bax is required. Fontaine et al. Found that NSAIDs acts on non small cells

 

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