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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrant arachidonic acid metabolism has recently received intensive attention in the field of cancer research. Recent discoveries regarding the long-term cardiovascular side effects of cyclooxygenase 2 inhibitors have cast doubts on their use for cancer chemoprevention. Although such a problem does not undermine the importance of cyclooxygenase 2 as a cancer chemopreventive target, investigation into other AA-metabolizing pathways that are also important in inflammation and inflammation-associated carcinogenesis is necessary. Here, the important role of the 5-lipoxygenase pathway in carcinogenesis is reviewed. Inhibition of the 5-lipoxygenase pathways clearly has chemopreventive effects on various cancers, and hence further studies on its enzymes, metabolites and receptors for cancer chemoprevention and therapy are warranted.
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PMID:Five-lipoxygenase pathway of arachidonic acid metabolism in carcino-genesis and cancer chemoprevention. 1710 May 67

The objective of this study was to determine the effects of 5-lipoxygenase (5-LO) inhibitors on the incidence of benzo(a)pyrene-induced pulmonary adenomas in female A/J mice. Two novel compounds, S-29606 and S-30621, and the Food and Drug Administration-approved Zileuton were investigated. S-29606 and S-30621 were selected from a group of similar active structures on the basis of local versus systemic 5-LO inhibitory activity. Preliminary studies found them to lack oral bioavailability, in direct contrast to Zileuton. Treatment was initiated 1 week following exposure to the carcinogen benzo(a)pyrene. Both S-29606 and S-30621 were dosed via nose-only inhalation 5 days a week, for 16 weeks, whereas Zileuton was administered orally. Dose levels for S-29606 and S-30621 were determined to be 220 and 430 microg/kg for the low- and high-dose groups, respectively, whereas the dose of Zileuton was 245 mg/kg. Both test compounds exhibited a significant reduction of pulmonary adenomas, compared with a positive control for high and low doses, P < 0.05. Additionally, a dose response for both S-29606 and S-30621 was observed when compared with placebo. Despite a dose 575 times greater than that of the novel test compounds, orally administered Zileuton did not produce a reduction in adenoma occurrence. The findings of this study offer compelling preliminary data for the use of S-29606 and S-30621 in further investigations of the treatment of pulmonary adenomas and support the use of inhalation drug delivery as an alternate to oral delivery for these compounds.
Carcinogenesis 2007 May
PMID:Effects of novel 5-lipoxygenase inhibitors on the incidence of pulmonary adenomas in the A/J murine model when administered via nose-only inhalation. 1711 45

The metabolism of arachidonic acid by either cyclooxygenase or lipoxygenase is believed to play an important role in carcinogenesis. Leukotriene (LT) D4 is a proinflammmatory mediator derived from arachidonic acid through various enzymatic steps, and 5-lipoxygenase is an important factor in generating LTD4. We investigated LTD4 receptor (cysteinyl LT1 receptor: CysLT1R) expression in prostate cancer (PC), as well as the effects of CysLT1R antagonist on cell proliferation in PC cell lines. CysLT1R expression in PC patients, prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues were examined. CysLT1R expression was detected by immunohistochemistry. Effects of CysLT1R antagonist on PC cell growth were examined by MTT assay. Flow cytometry and Hoechst staining were used to determine whether or not the CysLT1R antagonist induces apoptosis. Initially, only slight CysLT1R expression was detected in BPH and NP tissues and marked CysLT1R expression was detected in PIN and PC tissues. CysLT1R expression was higher in high-grade cancer than in low-grade cancer. Furthermore, CysLT1R antagonist caused marked inhibition of PC cells in a concentration- and time-dependent manner through early apoptosis. In conclusion, CysLT1R is induced in PC, and the results suggest that CysLT1R antagonist may mediate potent anti-proliferative effects of PC cells. Thus, the target of CysLT1R may become a new therapy in the treatment of PC.
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PMID:Overexpression of cysteinyl LT1 receptor in prostate cancer and CysLT1R antagonist inhibits prostate cancer cell growth through apoptosis. 1754 53

The arachidonic acid-metabolizing enzymes cyclooxygenase-2 (COX-2) or 5-lipoxygenase (5-LOX) are overexpressed during lung carcinogenesis and their end products (e.g.; PGE2, 5-HETE, and LTB4) have been implicated in tumor development. Recently, COX-2 inhibitors (e.g.; celecoxib) and 5-LOX inhibitors (e.g.; MK886 and REV5901) used as single agents have shown promising activities in the treatment and chemoprevention of cancer. However, little is known about the effects of combinations of these inhibitors. We found that simultaneous treatment of premalignant and malignant human lung cell lines with celecoxib, MK886, and REV5901 is more potent in growth suppression and induction of cell death than single or dual combination of these agents. However, their sensitivity to the inhibitors was not directly associated with the expression of COX-2, 5-LOX, or 5-LOX-activating protein (FLAP), but correlated with the production of corresponding metabolites. Furthermore, partial protection of cell death was observed when PGE2 and/or 5-HETE was added to cell cultures treated with celecoxib, MK886, and REV5901 simultaneously. Our data indicate that a triple drug combination of distinct inhibitors of the eicosanoid metabolism at clinically feasible concentrations were more effective than each agent alone suggesting further investigations.
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PMID:Simultaneous inhibition of COX-2 and 5-LOX activities augments growth arrest and death of premalignant and malignant human lung cell lines. 1755 58

The metabolism of arachidonic acid through lipoxygenase pathways leads to the generation of various biologically active eicosanoids. The expression of these enzymes vary throughout the progression of various cancers, and thereby they have been shown to regulate aspects of tumor development. Substantial evidence supports a functional role for lipoxygenase-catalyzed arachidonic and linoleic acid metabolism in cancer development. Pharmacologic and natural inhibitors of lipoxygenases have been shown to suppress carcinogenesis and tumor growth in a number of experimental models. Signaling of hydro[peroxy]fatty acids following arachidonic or linoleic acid metabolism potentially effect diverse biological phenomenon regulating processes such as cell growth, cell survival, angiogenesis, cell invasion, metastatic potential and immunomodulation. However, the effects of distinct LOX isoforms differ considerably with respect to their effects on both the individual mechanisms described and the tumor being examined. 5-LOX and platelet type 12-LOX are generally considered pro-carcinogenic, with the role of 15-LOX-1 remaining controversial, while 15-LOX-2 suppresses carcinogenesis. In this review, we focus on the molecular mechanisms regulated by LOX metabolism in some of the major cancers. We discuss the effects of LOXs on tumor cell proliferation, their roles in cell cycle control and cell death induction, effects on angiogenesis, migration and the immune response, as well as the signal transduction pathways involved in these processes. Understanding the molecular mechanisms underlying the anti-tumor effect of specific, or general, LOX inhibitors may lead to the design of biologically and pharmacologically targeted therapeutic strategies inhibiting LOX isoforms and/or their biologically active metabolites, that may ultimately prove useful in the treatment of cancer, either alone or in combination with conventional therapies.
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PMID:Lipoxygenase metabolism: roles in tumor progression and survival. 1794 11

Pancreatic cancer patients have an abysmal prognosis because of late diagnosis and lack of therapeutic options. Pancreatic intraepithelial neoplasias (PanINs), the precursor lesions, are a potential target for chemoprevention. Targeting eicosanoid pathways is an obvious choice because 5-lipoxygenase (5-LOX) has been suggested as a tumor promoter in pancreatic carcinogenesis. Here we provide evidence that 15-lipoxygenase-1 (15-LOX-1) expression and activity may exert antitumorigenic effects in pancreatic cancer. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis showed absence or very weak expression of 15-LOX-1 in all pancreatic cancer cell lines tested. 15-LOX-1 was strongly stained in normal ductal cells, tubular complexes, and centroacinar cells, but no staining was seen in islets, cancer cells, PanIN lesions, or in tumor cells in lymph node metastases, indicating that 15-LOX-1 expression is lost during tumor development in human pancreas. Overexpression of 15-LOX-1 in pancreatic tumor cells or treatment with its arachidonic acid-derived metabolite resulted in decreased cell growth. These findings provide evidence that loss of 15-LOX-1 may play an important role in pancreatic carcinogenesis, possibly as a tumor suppressor gene. Thus, induction of 15-LOX-1 expression may be an attractive option for the prevention and treatment of pancreatic cancer.
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PMID:15-lipoxygenase-1 production is lost in pancreatic cancer and overexpression of the gene inhibits tumor cell growth. 1803 Mar 60

Nowadays, no data are available concerning the potential use of dual cyclooxygenase (COX)/5-lipoxygenase (LOX) inhibitors as anticancer agents in colon cancer treatment. Here, we report, for the first time, that the dual COX/5-LOX inhibitor licofelone triggers apoptosis in a dose- and time-dependent manner in HCA-7 colon cancer cells. Induction of apoptosis was related to the recruitment of the intrinsic mitochondrial apoptotic pathway, as shown by loss in mitochondrial membrane potential, cytochrome c release, caspase-9 and 3 activation and poly-(ADP-ribose)polymerase-1 cleavage. Moreover, licofelone induced the cleavage of the full-length p21(Bax) into p18(Bax), a more potent inducer of the apoptotic process than the uncleaved form. Pre-treatment of HCA-7 cells with the pan-caspase inhibitor z-VAD-fmk significantly blocked licofelone-induced apoptosis, confirming that this process occurred primarily in a caspase-dependent pathway. We also present evidences that licofelone was able to affect the arachidonic acid (AA) cascade, as it blocked the activity of 5-LOX and COX enzymes, and it induced, through the phosphorylation of cytoplasmic phospholipase A(2) (cPLA(2)), the release of unesterified AA from HCA-7 membrane phospholipids. However, apoptosis induction was not related to the ability of licofelone to affect the AA cascade, since neither exogenous prostaglandin E(2) and leukotriene B(4) addition, nor pharmacological inhibition of cPLA(2), was able to rescue HCA-7 cells from apoptosis. Even if further studies are needed to clarify the mechanism of licofelone-induced apoptosis, this study suggests that this drug, as well as similar dual COX/5-LOX inhibitors, may represent a novel and promising approach in colon cancer treatment.
Carcinogenesis 2008 Feb
PMID:Licofelone, a dual COX/5-LOX inhibitor, induces apoptosis in HCA-7 colon cancer cells through the mitochondrial pathway independently from its ability to affect the arachidonic acid cascade. 1803 73

Ovarian cancer is a major cause of lethality from gynecological malignancies, and there is a lack of reliable and specific serum markers for this disease. Eicosanoid-related enzymes have previously been implicated in the pathogenesis of various types of cancer, but little is known about the relevance of lipoxygenase isoforms in ovarian cancer and the results on cyclooxygenases are conflicting. For this study, we quantified the expression of eicosanoid-related enzymes (cyclooxygenase-1 and cyclooxygenase-2, 15-lipoxygenase-1 and lipoxygenase-2, 5-lipoxygenase) in normal and malignant human ovarian tissue by real-time polymerase chain reaction and found a 22-fold elevated expression of 15-lipoxygenase-2 in malignant specimens when compared with normal ovarian tissue (P=0.001). In ovarian carcinoma metastases, expression of the enzyme was also augmented (20-fold upregulation, P=0.004). For 15-lipoxygenase-1 and cyclooxygenase-2, we did not observe differential expression, but there was a trend for increased steady-state concentrations of cyclooxygenase-1 (P=0.1 for ovarian carcinoma, P=0.011 for metastases) and 5-lipoxygenase (P=0.1 for ovarian carcinoma, P=0.018 for metastases, respectively). These data indicate that expression of 15-lipoxygenase-2 mRNA is strongly augmented during ovarian carcinogenesis and that the enzyme may constitute a suitable candidate as a tumor marker.
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PMID:15-Lipoxygenase-2 is differentially expressed in normal and neoplastic ovary. 1809 Jan 32

To identify the role of eicosanoid-mediated pathways for gastric carcinogenesis, the expression of enzymes (COX-1, COX-2, 5-LOX) and receptors (BLT-1, CysLTR(1)) were immunohistochemically studied in H. pylori positive patients with a risk gastritis phenotype and either successful or unsuccessful eradication (n=12, each; followed up for a median of 5 years). Gastric cancer risk index improved significantly after successful eradication (p<0.001). Semiquantitative immunohistochemistry revealed distinct significant changes in the expression patterns for COX-2, CysLTR1, COX-1 and BLT-1 depending on the eradication outcome, whereas 5-LOX expression was not altered. These results suggest an involvement of the COX-LOX pathway in gastric carcinogenesis.
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PMID:The long-term effect of Helicobacter pylori eradication on COX-1/2, 5-LOX and leukotriene receptors in patients with a risk gastritis phenotype--a link to gastric carcinogenesis. 1857 38

Aberrant arachidonic acid metabolism, especially altered cyclooxygenase and 5-lipoxygenase (LOX) activities, has been associated with chronic inflammation as well as carcinogenesis in human oral cavity tissues. Here, we examined the effect of Zyflamend, a product containing 10 concentrated herbal extracts, on development of 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced inflammation and oral squamous cell carcinoma (SCC). A hamster cheek pouch model was used in which 0.5% DMBA was applied topically onto the left cheek pouch of male Syrian golden hamsters either three times per week for 3 weeks (short term) or 6 weeks (long term). Zyflamend was then applied topically at one of three different doses (25, 50 and 100 microl) onto the left cheek pouch three times for 1 week (short-term study) or chronically for 18 weeks. Zyflamend significantly reduced infiltration of inflammatory cells, incidence of hyperplasia and dysplastic lesions, bromodeoxyuridine-labeling index as well as number of SCC in a concentration-dependent manner. Application of Zyflamend (100 microl) reduced formation of leukotriene B(4) (LTB(4)) by 50% compared with DMBA-treated tissues. The reduction of LTB(4) was concentration dependent. The effect of Zyflamend on inhibition of LTB(4) formation was further confirmed with in vitro cell-based assay. Adding LTB(4) to RBL-1 cells, a rat leukemia cell line expressing high levels of 5-LOX and LTA(4) hydrolase, partially blocked antiproliferative effect of Zyflamend. This study demonstrates that Zyflamend inhibited LTB(4) formation and modulated adverse histopathological changes in the DMBA-induced hamster cheek pouch model. The study suggests that Zyflamend might prevent oral carcinogenesis at the post-initiation stage.
Carcinogenesis 2008 Nov
PMID:Zyflamend reduces LTB4 formation and prevents oral carcinogenesis in a 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced hamster cheek pouch model. 1868 69


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