Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding of angiotensin II on the angiotensin II type-1 receptor induces cell growth, while triggering via the angiotensin II type-2 (AT(2)) receptor causes an opposing effect of growth inhibition and apoptosis. AT(2) receptor stimulation has also been shown to enhance inducible nitric oxide synthase (iNOS) expression, an enzyme associated with cancer. To study the involvement of the angiotensin II receptors and iNOS in the carcinogenesis of human breast, we visualised both factors in tissues from patients with hyperplasia, ductal carcinoma in situ (DCIS) and invasive carcinoma using immunocytochemistry and in situ hybridisation. In normal ducts, levels for AT(2) protein and mRNA are low, but these are markedly increased in all pathological tissues. While in normal tissue both negative and positive ducts are found, the staining patterns in hyperplasia, DCIS and invasive carcinoma have a homogeneous positive appearance. Similarly, iNOS enzyme expression was very low in the ductal epithelium of normal tissues, but highly increased in all pathologies, with the highest expression found in hyperplastic ducts. Three human cell lines were assayed for the presence of AT(2) receptor. Normal HMec 1001-3 cells were weakly positive, but only one of the adenocarcinoma cell lines, designated SK-BR-3, was shown to express both AT(2) protein and its mRNA. We show that AT(2) receptor and iNOS overexpression are associated with breast disease, further confirming the involvement of the components of the renin-angiotensin system in the aetiology of breast cancer.
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PMID:Increased angiotensin II type-2 receptor density in hyperplasia, DCIS and invasive carcinoma of the breast is paralleled with increased iNOS expression. 1181 93

Primary sclerosing cholangitis (PSC) is an idiopathic inflammatory disorder of the biliary tract characterized by diffuse biliary tract stricture formation, progressive chronic cholestasis and the development of secondary biliary cirrhosis. Biliary tract ischemia can produce morphological changes identical to PSC. We propose the existence of a localized renin-angiotensin system within the liver and extend the hypothesis that aberrant production of angiotensin II within the portal tract is the critical event contributing to the pathogenesis of PSC. A chronic reparative and proliferative state caused by chronic ischemia may promote carcinogenesis. Proof of this hypothesis will have implications for future therapeutic approaches given that current treatments for PSC aimed at reducing inflammation or the effects of cholestasis have proven ineffective.
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PMID:Aberrant local renin-angiotensin II responses in the pathogenesis of primary sclerosing cholangitis. 1278 43

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide hormone of the renin-angiotensin system with vasodilator and anti-proliferative properties. Human adenocarcinoma SK-LU-1 and A549 cells as well as non-small lung cancer SK-MES-1 cells were treated with serum in the presence and absence of Ang-(1-7), to determine whether Ang-(1-7) inhibits the growth of lung cancer cells. Ang-(1-7) caused a significant reduction in serum-stimulated growth in all three lung cancer cell lines. Treatment with Ang-(1-7) resulted in both a dose- and time-dependent reduction in serum-stimulated DNA synthesis in all three cell lines, with IC(50)'s in the sub-nanomolar range. The Ang-(1-7) receptor antagonist [D-Ala(7)]-Ang-(1-7) blocked the attenuation of the serum-stimulated DNA synthesis of SK-LU-1 cells by Ang-(1-7), while neither AT(1) nor AT(2) angiotensin receptor subtype antagonists prevented the response to the heptapeptide. MAS mRNA and protein, a receptor for Ang-(1-7), was detected in the three lung cancer cell lines, suggesting that the anti-proliferative effect of Ang-(1-7) in the cancer cells may be mediated by the non-AT(1), non-AT(2), AT((1-7)) receptor MAS. Other angiotensin peptides [Ang I, Ang II, Ang-(2-8), Ang-(3-8) and Ang-(3-7)] did not attenuate mitogen-stimulated DNA synthesis of SK-LU-1 cells, demonstrating that Ang-(1-7) selectively inhibits SK-LU-1 cancer cell growth. Pre-treatment of SK-LU-1 cells with 10 nM Ang-(1-7) reduced serum-stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1 and ERK2, indicating that the anti-proliferative effects may occur, at least in part, through inhibition of the ERK signal transduction pathway. The results of this study suggest that Ang-(1-7) inhibits lung cancer cell growth through the activation of an angiotensin peptide receptor and may represent a novel chemotherapeutic and chemopreventive treatment for lung cancer.
Carcinogenesis 2004 Nov
PMID:Inhibition of human lung cancer cell growth by angiotensin-(1-7). 1528 77

Angiotensin-I converting enzyme inhibitors (ACE-Is) are commonly used as safe antihypertensive agents, and it has recently been suggested that they decrease the risk of cancer development. Recent studies have revealed that the renin-angiotensin system (RAS) is involved in the development of many types of tumor. Angiotensin-II (AT-II) has many biological effects, including neo-vascularization, which plays a pivotal role in tumor development. AT-II induces a potent angiogenic factor, namely the vascular endothelial growth factor (VEGF). Some studies have proven that several ACE-Is are potent inhibitors of experimental tumor development and angiogenesis at clinically comparable doses. VEGF expression in tumors is also significantly suppressed by ACE-Is. When used in combination with the conventional anti-cancer drugs, ACE-Is exert more potent anti-tumor activities as compared with either single agent, in addition to suppression of the intra-tumoral angiogenesis. Furthermore, ACE-Is reportedly not only suppress tumor growth but also attenuate the carcinogenesis process in which angiogenesis is involved. Since ACE-Is are already in widespread clinical case without any serious adverse effects, they may represent a potential new strategy for cancer therapy and chemoprevention.
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PMID:Angiotensin-I converting enzyme inhibitors as potential anti-angiogenic agents for cancer therapy. 1557 13

The searches for drugs that exhibit antineoplastic activity and regulate blood pressure are among the most prevalent and compelling research activities today. Amazingly, there is ample precedence for the antiproliferative action of vitamin-D-related compounds and their role as endocrine suppressors of renin biosynthesis. We have recently synthesized a number of novel calcitriol analogs of the gemini family and originally selected for further studies an epimeric pair related to 19-nor-calcitriol whose 21-methyl group was replaced by a 5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)-2-pentynyl group. While maintaining the acceptable calcemic responses, the IC50 concentrations of interferon-gamma release were reduced and the antiproliferative activity and inhibition of renin mRNA expression enhanced. Replacing the geminal methyl groups on the calcitriol-related side chain of these gemini compounds with trideuteriomethyl moieties further boosted the potency in the colon cancer model in mice some 10-fold, reduced NMU-induced breast cancer carcinogenesis in rats and decreased the IC(50) values for renin mRNA inhibition into the pM range.
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PMID:Calcitriol derivatives with two different side chains at C-20 III. An epimeric pair of the gemini family with unprecedented antiproliferative effects on tumor cells and renin mRNA expression inhibition. 1725 79

Angiotensin II has been shown to be a cytokine especially acting as a growth factor. A local renin-angiotensin system has been identified in the prostate gland, and the physiologic function of angiotensin II seems to be similar in prostate cancer, as we previously reported. In the present study, we explored the biological role of angiotensin II in oxidative stress of prostate cancer cells. Activated Akt was determined, and the expression of oxidative stress-related proteins (p47phox, manganese superoxide dismutase 2, glutathione peroxidase) was examined by Western blotting in LNCaP cells, which were stimulated with angiotensin II and/or an angiotensin II receptor type 1 blocker, candesartan. To examine DNA damage induced by angiotensin II, 8-hydroxy-2'-deoxyguanosine was determined, and Western blots were analyzed to detect checkpoint proteins including p53, Chk2, and cdc2. Immunocytochemical studies of inducible nitric oxide synthase and superoxide anion radical (O(2)(-)) were done in LNCaP cells stimulated with angiotensin II. The phosphorylation of Akt was induced by angiotensin II treatment and inhibited by candesartan, as well as by LY294002, an inhibitor of phosphoinositide 3-kinase. Oxidative stress-related proteins were up-regulated by angiotensin II and inhibited by pretreatment with candesartan or catalase. The level of 8-hydroxy-2'-deoxyguanosine was increased by angiotensin II and conversely decreased by candesartan. Immunocytochemical studies showed that angiotensin II enhanced an inflammatory marker, inducible nitric oxide synthase, and the production of O(2)(-) radical. The hypothesis that angiotensin II has the potential to induce oxidative stress, which may be implicated in carcinogenesis of the prostate gland through long-term exposure to chronic inflammation is proposed.
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PMID:Angiotensin II induces oxidative stress in prostate cancer. 1831 86

The renin-angiotensin system (RAS) is usually associated with its systemic action on cardiovascular homoeostasis. However, recent studies suggest that at a local tissue level, the RAS influences tumour growth. The potential of the RAS as a target for cancer treatment and the suggested underlying mechanisms of its paracrine effects are reviewed here. These include modulation of angiogenesis, cellular proliferation, immune responses and extracellular matrix formation. Knowledge of the RAS has increased dramatically in recent years with the discovery of new enzymes, peptides and feedback mechanisms. The local RAS appears to influence tumour growth and metastases and there is evidence of tissue- and tumour-specific differences. Recent experimental studies provide strong evidence that drugs that inhibit the RAS have the potential to reduce cancer risk or retard tumour growth and metastases. Manipulation of the RAS may, therefore, provide a safe and inexpensive anticancer strategy.
Carcinogenesis 2008 Sep
PMID:The renin-angiotensin system and malignancy. 1863 55

Increased activity of the renin angiotensin system with enhanced levels of angiotensin II leads to oxidative stress with endothelial dysfunction, hypertension, and atherosclerosis. Epidemiologic studies revealed a higher cancer mortality and an increased kidney cancer incidence in hypertensive patients. Because elevated angiotensin II levels might contribute to carcinogenesis, we tested whether angiotensin II induces DNA damage in the kidney. In isolated perfused mouse kidneys, as little as 1 nmol/L angiotensin II caused a significant increase in DNA strand breaks, measured with the comet assay. This damage was independent of the hemodynamic effect of angiotensin II and mediated by the angiotensin II type 1 receptor. Angiotensin II also caused double-strand breaks in the cells of the isolated perfused kidney, detected with an antibody against the double-strand break marker gamma-H2AX. Studies in cell culture allowed further characterization of the DNA damage induced by angiotensin II. Single- and double-strand breaks, abasic sites, and 7,8-dihydro-8-oxo-guanine, all types of oxidative DNA lesions, were detected in angiotensin II-treated renal cells. The majority of detected strand breaks was repaired within 1 hour, but double-strand breaks increased and persisted for at least 24 hours.
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PMID:Angiotensin II induces DNA damage in the kidney. 1901 Aug 96

Although a low prevalence of cancer in hypertensive patients receiving angiotensin converting enzyme inhibitors was reported, the molecular mechanisms have not been elucidated. It is known that the Angiotensin- II (Ang- II) plays a fundamental role not only as a vasoconstrictor in controlling blood pressure and electrolyte/fluid homeostasis, but also as a mitogenic factor through the Ang- II type-1 (AT1) receptor in cardiovascular cells. Recently, there has been increasing evidence that the renin-angiotensin system (RAS) is implicated in the development of various cancers. Ang- II has been demonstrated to be a cytokine, especially acting as a growth factor. Of interest, the physiological function of Ang- II seems to be similar in prostate cancer and stromal cells as we previously reported. AT1 receptor blockers (ARBs), a class of anti hypertensive agent, have the potential to inhibit the growth of prostate cancer cells and tumors through the AT1 receptor. We conducted a pilot clinical study to examine whether ARBs were able to elicit an anti proliferative effect on prostate cancer clinically, resulting in a PSA decline of hormone refractory cancer or delaying PSA progression after radical prostatectomy. As a number of investigators have clarified that Ang- II induces oxidative stress in vascular cells, we reported the hypothesis that Ang- II generated in the prostate gland maybe a cause of oxidative stress linked to prostatic carcinogenesis. This review provides an insight into the key role of Ang- II and AT1 receptor, and the possibility of ARBs for molecular targeting of mitogenesis and angiogenesis in prostate cancer.
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PMID:[Role of renin-angiotensin system in prostate cancer]. 1969 59

The renin-angiotensin system (RAS) is well known for its vital involvement in body fluid homeostasis and circulation. However, very little research has been devoted to the impact of this regulatory system on the gastrointestinal (GI) system. This is surprising because the GI tract is fundamental for the intake and excretion of fluid and electrolytes (and nutrients), and it accommodates a large proportion of bodily haemodynamics and host defence systems. The RAS is well expressed and active in the GI tract, although the exact roles for the key mediator angiotensin II (Ang II) and its receptors in general, and the type 2 (AT( 2)) receptor in particular, are not completely settled. There are several reports showing Ang II regulation of intestinal fluid and electrolyte transport. For example, mucosaprotective duodenal bicarbonate-rich secretion is inhibited by Ang II via type 1 (AT(1)) receptor-mediated facilitation of sympathoadrenergic activity, but this secretory process can also be stimulated by Ang II via AT(2) receptors. Novel data from human oesophagus and jejunum suggest that the AT(1) receptor mediates muscular contractions and that the AT(2) receptor regulates epithelial functions. Data are accumulating suggesting involvement of AT(1) and AT(2) receptors in GI inflammation and carcinogenesis. The picture of the RAS and AT( 2) receptor in the GI tract is, however, far from complete. Much more basic research is needed with regard to GI pathophysiology before concluding clinical significance and potential applicability of pharmacological interferences with the RAS.
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PMID:The angiotensin II type 2 receptor and the gastrointestinal tract. 1986 52


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