5-脂氧合酶与食管癌

食管癌是严重威胁我国人们生命健康的恶性肿瘤,深入了解食管浸润、转移的机制,寻求更新、更好的治疗靶点具有重要意义.越来越多的研究显示,以不饱和脂肪酸氧化代谢为标靶探求抗癌的干预措施在临床前期的研究中具有广阔的前景.肿瘤发生学的研究表明,不饱和脂肪酸必须经历氧化代谢来促进肿瘤生成.5-脂氧合酶（5-LOX）和环氧合酶-2（COX-2）分别是花生四烯酸脂氧合酶、环氧合酶两条代谢途径中重要的限速酶.COX-2参与调节肿瘤细胞的增生与凋亡、肿瘤微血管的生成、癌细胞的侵袭与转移以及宿主免疫系统的抑制等多个病理生理过程.食管癌组织中有COX-2的高表达,并与预后密切相关[1,2].人们已经在探索COX-2的抑制剂在肿瘤防治中的作用.随着研究的深入,参与花生四烯酸代谢的另一关键酶类-脂氧合酶受到了越来越多的关注,有学者发现NSAIDs可通过花生四烯酸代谢的另一主要途径-脂氧合酶途径而触发凋亡[3].不断增多的数据表明,脂氧合酶代谢途径有望成为一个新的抗肿瘤靶点.     

环氧合酶-2与消化系统肿瘤

环氧合酶(cyclooxygenase)是花生四烯酸代谢的关键限速酶。其亚型COX-2具有特殊的生物学特性,在肿瘤的发生发展中起重要作用。资料表明,NSAIDs是通过抑制COX-2来发挥抗肿瘤作用的。因而,选择性COX-2抑制剂的研制有可能为恶性肿瘤的治疗开辟新的途径。     

花生四烯酸代谢通路与胰腺癌

花生四烯酸(arachidonic acid,AA)是人体一种必需脂肪酸,该脂肪酸含有20个碳原子,4个双键,是5,8,11,14-二十碳四烯酸.其代谢有两条途径: 环氧化酶(COX)和脂氧合酶(LOX).研究表明其代谢限速酶COX和LOX在胰腺癌中呈高表达,AA代谢产物抑制COX和LOX通路,具有抑制肿瘤生长,促进肿瘤细胞凋亡,抑制肿瘤细胞转移等功能.非选择性和选择性COX或LOX抑制剂被用来尝试治疗胰腺及其他肿瘤.     

环氧合酶—2与消化系统肿瘤

环氧合酶（cyclooxygenase）是花生四烯酸代谢的关键限速酶。其亚型COX－2具有特殊的生物学特性，在肿瘤的发生发展中起重要作用。资料表明，NSAIDs是通过抑制COX－2来发挥抗肿瘤作用的。因此，选择性COX－2抑制剂的研制有可能为恶性肿瘤的治疗开辟新的途径。     

COX-2与胃癌关系的研究进展

环氧合酶2是诱导性酶,在胃癌组织中高表达.主要参与胃癌的血管形成、诱导基因突变、抑制肿瘤免疫、抑制凋亡、改变黏附因子活性,促使肿瘤转移等,对胃癌的发生、发展、预后均起重要的作用.选择性环氧合酶抑制剂具有抑癌作用,有望成为胃癌治疗的基础药物之一.     

环氧合酶抑制剂在肝癌预防和治疗中的研究进展

研究显示在许多肿瘤中, 环氧合酶(COX)2及其产物过度表达. 非甾体类抗炎药可以抑制环氧合酶的活性, 从不同途径达到抑制肿瘤细胞的生长、诱导凋亡, 抑制血管形成、降低肿瘤的侵袭力和转移性. 肝癌是世界常见的恶性肿瘤之一, 预后较差, 形成机制尚未清楚, 其预防和治疗水平有限. 因此找到一种新的抗癌药物并研究其抗肝癌的作用机制,在肝癌的预防和治疗中有重要意义. 本文对COX抑制剂与肝癌形成和肝癌的预防和治疗中进展作一综述.     

环氧合酶-2和胰腺癌

胰腺癌目前发病率有上升的趋势,其死亡率非常高.环氧合酶-2（COX-2）在诸多肿瘤尤其是消化道肿瘤中起着重要作用,有研究发现COX-2在胰腺癌的发生、转移、治疗和化学预防中起着重要作用.本文就此作一综述.     

消化系统肿瘤治疗以环氧合酶-2和5-脂氧合酶双通路作为靶点的研究进展

花生四烯酸(arachidonic acid,AA)主要通过环氧合酶(cyclooxygenase,COX),脂氧合酶(lipoxygenase,LOX)通路代谢.研究表明,COX和LOX在多种人类肿瘤中呈高表达.其中,COX-2和5-LOX在某些肿瘤中还出现共同表达,其代谢产物在肿瘤的发生发展过程中起重要作用.     

NS-398影响基质金属蛋白酶-2及其抑制剂的表达

近年研究发现,选择性环氧合酶（COX）-2抑制剂具有抑制肿瘤细胞生长,促进其凋亡的作用.但是选择性COX-2抑制剂影响肿瘤细胞侵袭转移能力的报道较少,其影响基质金属蛋白酶（MMP）和基质金属蛋白酶抑制剂（TIMP）表达方面的报道尤其少见.因此,我们以选择性COX-2抑制剂NS-398作用于HepG2肝癌细胞株,观察MMP-2、TIMP-2表达的变化,探讨其在肿瘤侵袭和转移中的作用.     

环氧合酶-2与肝脏疾病的研究进展

环氧合酶-2是人体合成前列腺素的关键酶,参与炎症反应、细胞增殖与凋亡,在多种疾病中发挥作用.近年来研究发现,环氧合酶-2与肝脏疾病发生发展密切相关,选择性环氧合酶-2抑制剂有望成为临床治疗肝病的有效药物.本文就环氧合酶-2与肝脏疾病的研究进展作一综述.     

Anti-cancer effects of COX-2 inhibitors and their correlation with angiogenesis and invasion in gastric cancer

AIM: To observe the anti-cancer effects of COX-2 inhibitors and investigate the relationship between COX-2 inhibitors and angiogenesis, infiltration or metastasis in SGC7901 cancer xenografts. METHODS: Thirty athymic mice xenograft models with human stomach cancer cell SGC7901 were established and divided randomly into 3 groups of 10 each. Sulindac, one non-specific COX inhibitor belonging to non-steroidal anti-inflammatory drugs (a series of COX inhibitors known as NSAIDs) and celecoxib, one selective COX-2 inhibitor (known as SCIs) were orally administered to mice of treatment groups. Immunohistochemistry was used to examine the expression of PCNA, CD44v6 and microvessel density (MVD). Apoptosis was detected by using TUNEL assay. RESULTS: Tumors in sulindac and celecoxib groups were significantly smaller than those in control group from the second week after drug administration (P<0.01). In treatment group, the cell proliferation index was lower (P<0.05) and apoptosis index was higher (P<0.05) than those in control groups. Compared with the controls, microvessel density was reduced (P<0.01) and expression of CD44v6 on tumor cells was weakened (P<0.05) in treatment groups. CONCLUSION: COX-2 inhibitors have anticancer effects on gastric cancer. They play important roles in angiogenesis and infiltration or metastasis of stomach carcinoma. The anticancer effects of COX-2 inhibitors may include inducing apoptosis, suppressing proliferation, reducing angiogenesis and weakening invasiveness.     

Cyclooxygenase-2 as a target for anticancer drug development

The two isoforms cyclooxygenase-1 and -2 catalyze the initial step in the formation of prostaglandins in a variety of pathophysiological processes. More recently their role in carcinogenesis has become more evident. They seem to influence apoptosis, angiogenesis, and invasion, and play a role in the production of carcinogens. Usually, a high level of COX-2 expression is found in cancer cells. However, low COX-2 expression is observed in some cancers like prostate or breast cancer. This phenomenon is quite surprising and should influence on clinical trial designs. Large epidemiological trials studying users and non-users of aspirin have shown that cyclooxygenase (COX) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) could be of benefit against the development and growth of malignancies. Moreover, clinical trials in patients with familial adenomatosis polyposis syndrome have shown too the efficacy of non-selective COX inhibitors and recently also of selective COX-2 inhibitors in the reduction of the number and the size of colorectal polyps. However, a primary chemopreventive effect has not been demonstrated yet. NSAIDs are also supposed to have a preventive and growth inhibitory effect in extra-colonic epithelial malignancies. Several preclinical studies show promising results with combination treatments of either chemotherapy or radiotherapy with COX inhibitors. Preclinical studies with the simultaneous use of inhibitors of the epidermal growth factor receptor and COX-2 inhibitors have shown also promising results. Encouraging results with the first clinical trials combining chemotherapy with COX-2 inhibitors in patients with cancer in the advanced and neoadjuvant setting have recently been reported. However, NSAIDs effects in cancer cells are mediated not only by COX enzymes but also by interactions with downstream effectors of COX-2. Hence, we can state that targeting the COX-2 pathway is a promising strategy in the prevention and treatment of solid tumors. Ongoing trials are expected to answer - at least partly - the remaining questions concerning COX-2 and cancer.     

COX-2 inhibitors in inflammatory bowel disease: friends or foes?]

The cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostaglandins. COX-1 is constitutively expressed and is a critical housekeeping gene, whereas COX-2 is rapidly upregulated by growth factors and cytokines and thus responsible for inflammation. COX-2 is frequently overexpressed in colonic adenoma and carcinoma. Specific inhibitors of COX-2 have been shown to induce apoptosis in tumor cells and to inhibit tumor growth in animal models and in humans. Long-standing IBD patients have increased risk of developing colorectal cancer compared to general population. IBD-associated colorectal carcinogenesis is probably promoted by chronic inflammation and closely related to COX-2. In a recent study, powerful chemopreventive ability of selective COX-2 inhibitor was observed in colitis-related colon carcinogenesis in mouse model. But it was reported that even selective COX inhibitors aggravated the DSS-induced colonic inflammation. It is assumed that endogenous PGs are involved in the mucosal defense against DSS-induced colonic ulcerations which are produced by COX-1 at early phase and by COX-2 at late phase. Long-term use of COX-2 inhibitors for the chemoprevention of colitic cancer is needed to define their mechanism of action, that reduce side effects and have specific tumor target.     

环氧合酶—2蛋白在胃癌组织中的表达

流行病学调查发现长期使用非巢体类抗炎药（ＮＳＡＩＤｓ）的患者强肠癌发病率明显下降。ＮＳＡＩＤｓ能抑制环氧合酶（ＣＯＸ）,而ＣＯＸ－２在结肠癌的发生、发展中起一定作用。目的：调查ＣＯＸ－２蛋白在胃癌组织中的表达。方法：用免疫组化半定量方法检测ＣＯＸ－２和ＣＯＸ－１蛋白在胃癌及相应正常组织中的表达。结果：９７．１％（３３／３４）的胃癌组织中有ＣＯＸ－２蛋白表达,其强度明显高于正常胃窦粘膜,分伦型胃癌的     

Cyclooxygenases in hepatocellular carcinoma

Many epidemiological studies demonstrate that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase (COX) enzymes are well-known targets of NSAIDs. However, conventional NSAIDs non-selectively inhibit both the constitutive form COX-1, and the inducible form COX-2. Recent evidence indicates that COX-2 is an important molecular target for anticancer therapies. Its expression is undetectable in most normal tissues, and is highly induced by pro-inflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, malignant, and metastastic cancers, including hepatocellular carcinoma (HCC). Overexpression of COX-2 in patients with HCC is generally higher in welldifferentiated HCCs compared with less-differentiated HCCs or histologically normal liver, suggesting that COX-2 may be involved in the early stages of hepatocarcinogenesis, and increased expression of COX-2 in noncancerous liver tissue has been significantly associated with shorter disease-free survival in patients with HCC. In tumors, overexpression of COX-2 leads to an increase in prostaglandin (PG) levels, which affect many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness and metastatic potential of tumor cells. The availability of novel agents that selectively inhibit COX-2 (COXIB), has contributed to shedding light on the role of this molecule. Experimental studies on animal models of liver cancer have shown that NSAIDs, including both selective and non-selective COX-2 inhibitors, exert chemopreventive as well as therapeutic effects. However, the key mechanism by which COX-2 inhibitors affect HCC cell growth is as yet not fully understood. Increasing evidence suggests the involvement of molecular targets other than COX-2 in the antiproliferative effects of COX-2 selective inhibitors. Therefore, COX-inhibitors may use both COX-2-dependent and COX-2-independent mechanisms to mediate their antitumor properties, although their relative contributions toward the in vivo effects remain less clear. Here we review the features of COX enzymes, the role of the expression of COX isoforms in hepatocarcinogenesis and the mechanisms by which they may contribute to HCC growth, the pharmacological properties of COX-2 selective inhibitors, the antitumor effects of COX inhibitors, and the rationale and feasibility of COX-2 inhibitors for the treatment of HCC.     

Prostaglandin inhibitors and the chemoprevention of noncolonic malignancy.

Much has been learned about the role of NSAIDs as cancer preventives through epidemiologic and experimental studies. The pathways of carcinogenesis in the gastrointestinal tract are initiated by many different genetic, environmental, infective, and lifestyle factors. It is possible that the final common pathway of all these malignancies may have some common features. It is conceivable that head and neck, esophageal, gastric, and colorectal epithelial carcinogenesis all are influenced by or require COX-2 up-regulation as a step toward transformation. Intuitively, it is possible that selective COX-2 inhibitors may have a preventive role in all these epithelial malignancies. Today's challenge is to translate this information into clinical trials to define what role, if any, COX inhibition might play in the prevention of these malignancies.     

Cyclo-oxygenase inhibition in colorectal adenomas and cancer

Increasing evidence indicates that Non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), can reduce the number and size of adenomas in patients with familial adenomatous polyposis as well as the incidence of colorectal cancer. The COX enzyme family consists of the classic COX-1 and a second enzyme, COX-2, which is induced by various stimuli, such as mitogens and cytokines. While it is well proven that COX-2 overexpression is a central event in colorectal carcinogenesis, that prostaglandins (PGs) can contribute to tumorigenesis, and that COX-2 selective inhibitors are active chemopreventive agents, the molecular mechanisms by which NSAIDs exert their chemopreventive effect is not fully understood. However, significant advances have been made in understanding the interference of NSAIDs with the pathways that control cell growth and survival even independently from their COX-inhibiting properties, making their use attractive both alone and in combination with standard therapies in the treatment of advanced colorectal cancer. In addition, the recently recognized anti-angiogenic and radiosensitizer properties of COX-2 inhibitors support, further suggest their use in the adjuvant setting.     

COX-2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer

Lymphangiogenesis has been shown to promote lymph node metastasis in cancers, making it an important target in cancer therapy. Vascular endothelial growth factor (VEGF)-C is upregulated in various tumors/cancers and is one of the most potent growth factors for inducing lymphangiogenesis and promoting lymph node metastasis (LNM). Likewise, cyclooxygenase (COX)-2 plays major roles in carcinogenesis, tumor growth and metastasis via multiple mechanisms including inactivation of host antitumor immunity and promotion of tumor cell migration, tumor cell invasiveness and tumor-associated angiogenesis and lymphangiogenesis. We previously demonstrated an association between COX-2 and VEGF-C in an in vitro model of lung cancer. However, little is known about the regulation of VEGF-C by COX-2 in cervical cancer. In this study, we measured the COX-2 and VEGF-C expressions by immunohistochemistry in 23 LNM-positive and 20 LNM-negative cervical cancer specimens. We then examined the correlations among the expressions and the lymphatic microvessel density (LMVD) and ultrastructural changes to the lymphatic vessel walls by enzyme histochemical staining and electron microscopy. In addition, we used the HeLa cervical cancer cell line to explore the in vitro regulation of VEGF-C by COX-2 and its metabolite, PGE₂, using siRNA-mediated gene silencing and EP receptor blockade. The LNM-positive specimens exhibited significantly higher VEGF-C expression, COX-2 expression and LMVD than the LNM-negative specimens. Furthermore, there were strong correlations between the levels of COX-2 expression and the levels of VEGF-C expression and secretion and a significant positive association between the LMVD and LNM. siRNA-mediated knockdown of COX-2 expression inhibited VEGF-C mRNA expression while EP1 and EP4 receptor antagonists reduced the VEGF-C protein level and tyrosine phosphorylation of Src kinase. Moreover, inhibition of Src kinase with the tyrosine kinase inhibitor PP1 attenuated VEGF-C expression. Collectively, our data provide evidence for a clinical association between COX-2 and VEGF-C expressions in cervical cancer. EP1 and EP4 receptors may be involved in the COX-2-mediated regulation of VEGF-C protein and mRNA expressions. Src may be a downstream mediator of EP1 and EP4 receptors. COX-2 inhibition may diminish LNM by suppressing VEGF-C-mediated lymphangiogenesis.     

Role of cyclooxygenase-2 in the development and treatment of oesophageal adenocarcinoma

BACKGROUND: Various studies suggest that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are promising anticancer agents. Epidemiological studies have found that long-term use of NSAIDs is associated with a reduced incidence of colorectal, gastric and oesophageal cancers, while experimental and clinical studies have demonstrated that treatment with NSAIDs causes a statistically significant reduction in both the number and the size of polyps in familial adenomatous polyposis (FAP) patients. METHODS: In this review, the mechanisms by which NSAIDs exert their chemopreventive and antineoplastic effects are described. RESULTS: Although the precise anticancer actions of NSAIDs are not fully explained, they probably involve inhibition of cyclooxygenase (COX), which is the rate-limiting enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of this enzyme (COX-1 and COX-2) have been identified. COX-1 is constitutively expressed and considered to be a housekeeping gene, while COX-2 is not usually detectable in normal tissues, but can be readily induced in processes like inflammation, reproduction and carcinogenesis. The mechanisms by which COX-2 is thought to be involved in the carcinogenesis include resisting apoptosis, increasing cell proliferation, stimulating angiogenesis and modulating the invasive properties of cancer cells. CONCLUSION: This report reviews the mechanisms by which COX-2 can contribute to carcinogenesis, its role in prognosis, and the possible place of selective COX-2 inhibitors in the prevention and treatment of gastrointestinal malignancies, focusing particularly on oesophageal cancer.     

Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line

BACKGROUND & AIMS: Although bile acids have been implicated in colon cancer development, their role in biliary tract carcinogenesis remains unexplored. Because receptor tyrosine kinases and cyclooxygenase (COX)-2 have been implicated in carcinogenesis, we examined the hypothesis that bile acids modulate these enzymes in KMBC cells, a human cholangiocarcinoma cell line. METHODS: The effect of bile acids on epidermal growth factor receptor (EGFR) stimulation, mitogen-activated protein kinase (MAPK) activation, and COX-2 expression was evaluated. RESULTS: Bile acids both induced EGFR phosphorylation and enhanced COX-2 protein expression. Bile acid-induced EGFR phosphorylation was associated with subsequent activation of MAPK p42/44, p38, and c-Jun-N-terminal kinase (JNK). The MAPK inhibitors, PD098059 for MAP or extracellular signal-regulated kinase 1, SB203580 for p38, and BAY 37-9751 for Raf-1, blocked COX-2 induction by bile acids. However, inhibition of JNK activity did not block bile acid-mediated COX-2 induction. CONCLUSIONS: The results show that EGFR is activated by bile acids and functions to induce COX-2 expression by an MAPK cascade. This induction of COX-2 may participate in the genesis and progression of cholangiocarcinomas.