Inhibition of carcinogenesis in transgenic mouse models over-expressing 15-lipoxygenase in the vascular wall under the control of murine preproendothelin-1 promoter

Harats, Dror; Ben‐Shushan, Dikla; Cohen, Hofit; Gonen, Ayelet; Barshack, Iris; Goldberg, Iris; Greenberger, Shoshana; Hodish, Israel; Harari, Ayelet; Varda‐Bloom, Nira; Levanon, Keren; Grossman, Ehud; Chaitidis, Pavlos; Kühn, Hartmut; Shaish, Aviv

doi:10.1016/j.canlet.2005.02.017

Cited by 36 publications

(35 citation statements)

References 21 publications

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“…Our group has shown that interactions between 15-LOX-1 signaling and GATA-6, protein kinase G, histone deacetylase, and methyltransferase (which are upstream regulators) and PPAR-y and PPAR-g (which are downstream mediators) are COX-2-independent mechanisms involved in 15-LOX-1-induced apoptosis and anticarcinogenic activity (106)(107)(108)(109)(110)(111). The important role of 15-LOX-1 in carcinogenesis and as a target for cancer prevention recently has been confirmed by a number of research groups (112)(113)(114)(115)(116)(117).…”

Section: Molecular Targeting and The Risk Of Cancer Preventionmentioning

confidence: 99%

Reducing the “Risk” of Chemoprevention: Defining and Targeting High Risk—2005 AACR Cancer Research and Prevention Foundation Award Lecture

Lippman¹,

Lee²

2006

Cancer Research

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Two large-scale, phase III cancer prevention trials, the Breast Cancer Prevention Trial (BCPT) of tamoxifen and Prostate Cancer Prevention Trial (PCPT) of finasteride, concluded with strikingly positive and simultaneously problematic results: reduced cancer risks but a major adverse finding with each agent that prevented its widespread use in the community. For most moderate-risk people, such as those studied in the BCPT and PCPT, the benefit of reduced breast or prostate cancer does not outweigh the major risk of tamoxifen (endometrial cancer in the BCPT) or apparent risk of finasteride (high-grade prostate cancer in the PCPT). Promising interventions with biologically active substances are likely to have adverse, perhaps unforeseen effects, especially with long-term preventive use. Acceptance of such agents will depend heavily on the level of cancer risk of the target population. This article outlines research in molecularly identified high-risk oral intraepithelial neoplasia that creates the clinical opportunity for optimizing the riskbenefit ratio of agents to prevent oral cancer. Two other major research efforts focused on improving preventive agent risk-benefit ratios are molecular-targeted research designed to target away from known adverse signaling pathways and multidisciplinary research based on the PCPT that will develop comprehensive models of prostate cancer risk (especially of aggressive prostate cancer) and pharmacoecogenetic models for identifying high-risk men most likely to benefit from (and not be harmed by) finasteride or similar (5A-reductase inhibiting) agents. Defining and targeting high-risk populations, developing molecular-targeted approaches, and developing accurate pharmacoecogenetic models promise to reduce the risk of chemoprevention and ultimately to reduce the risk and burden of major cancers. (Cancer Res 2006; 66(6): 2893-903) For decades, the mantra of cancer chemoprevention has been: ''Find effective agents with relatively little or no toxicity for preventing cancer in relatively healthy people.'' In pursuing this goal, trials big and small of a myriad of agents with relatively less or more toxicity reached at least a temporary plateau with the doubleedged results of the Breast Cancer Prevention Trial (BCPT) published in 1998 (1) and Prostate Cancer Prevention Trial (PCPT) published in 2003 (2). Tamoxifen reduced the risk of breast cancer by almost 50% among the 13,388 randomized women (moderately high risk) of the BCPT but also increased these women's risk of endometrial cancer. Finasteride produced a 25% overall reduction in prostate cancer prevalence among the 18,882 randomized men (ages z55 years) of the PCPT but also surprisingly seemed to increase these men's risk of high-grade prostate cancer. Despite the established preventive effects of tamoxifen and finasteride, the important risks/side effects associated with these agents produced a widespread resistance to their use for preventing breast or prostate cancer.Important work in the same moderate-risk vein con...

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Section: Molecular Targeting and The Risk Of Cancer Preventionmentioning

confidence: 99%

Reducing the “Risk” of Chemoprevention: Defining and Targeting High Risk—2005 AACR Cancer Research and Prevention Foundation Award Lecture

Lippman¹,

Lee²

2006

Cancer Research

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“…The potential antitumorigenic effect of 15-LO-1 could also be related to angiogenesis. 26 However, the effect of 15-LO-1 on angiogenesis induced by VEGF is not known. Therefore, we wanted to clarify the effects of 15-LO-1 on the induction of angiogenesis by VEGF family members in the well-established rabbit hindlimb model.…”

Section: Viita Et Al 15-lo-1 Blocks Vegf-and Plgf-induced Angiogenesismentioning

confidence: 99%

15-Lipoxygenase-1 Prevents Vascular Endothelial Growth Factor A– and Placental Growth Factor–Induced Angiogenic Effects in Rabbit Skeletal Muscles via Reduction in Growth Factor mRNA Levels, NO Bioactivity, and Downregulation of VEGF Receptor 2 Expression

Viita

Markkanen

Eriksson

et al. 2008

Circulation Research

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Abstract-Human 15-lipoxygenase-1 (15-LO-1) is an oxidizing enzyme capable of producing reactive lipid hydroperoxides. 15-LO-1 and its products have been suggested to be involved in many pathological conditions, such as inflammation, atherogenesis, and carcinogenesis. We used adenovirus-mediated gene transfers to study the effects of 15-LO-1 on vascular endothelial growth factor (VEGF)-A 165 -and placental growth factor (PlGF)-induced angiogenesis in rabbit skeletal muscles. 15-LO-1 significantly decreased all angiogenic effects induced by these growth factors, including capillary perfusion, vascular permeability, vasodilatation, and an increase in capillary number. The effects are attributable to the reduction in the amount of VEGF-A 165 and PlGF transcripts by 15-LO-1, resulting in reduced protein expression. The most likely mediator of the VEGF family-induced capillary vasodilatation is nitric oxide (NO), which is produced by NO synthases. Endothelial NO synthase protein expression and NO synthase activity were significantly induced by VEGF-A 165 , and these inductions were reduced by 15-LO-1. VEGF-A 165 induces its angiogenic effects primarily via vascular endothelial growth factor receptor (VEGFR)2, and also PlGF mediates angiogenic signaling via VEGFR2, even though it binds to VEGFR1. VEGFR2 expression is induced by peroxisome proliferator-activating receptor ␥. We showed by quantitative RT-PCR and immunohistochemistry that expression of endogenous rabbit peroxisome proliferator-activating receptor ␥ and VEGFR2 were significantly increased in the growth factor-transduced muscles, but these inductions were efficiently prevented by 15-LO-1. In conclusion, the results suggest that expression of 15-LO-1 has an efficient antiangiogenic effect in vivo via reduction in growth factor mRNA levels, NO bioactivity, and VEGFR2 expression. Key Words: 15-lipoxygenase Ⅲ vascular endothelial growth factor Ⅲ vascular endothelial growth factor receptor Ⅲ peroxisome proliferator-activating receptor Ⅲ angiogenesis H uman 15-lipoxygenase-1 (15-LO-1) is a lipidperoxidizing enzyme capable of introducing molecular oxygen to polyunsaturated fatty acids either in free form or in more complex compounds, such as biological membranes, phospholipids, cholesterol esters, and plasma lipoproteins. 1,2 The primary 15-LO-1 products from arachidonic acid and linoleic acid are 15-hydroperoxyeicosatetraenoic acid and 13-hydroperoxyoctadecadienoic acid, respectively. 1 15-LO-1 belongs to the class of reticulocyte-type lipoxygenases, which under basal conditions are mainly expressed in reticulocytes and eosinophils. 2 In reticulocytes, 15-LO-1 reacts with mitochondrial membrane lipids, initiating a controlled breakdown of mitochondria during the reticulocyte maturation process. 3 The physiological role of 15-LO-1 in cells other than reticulocytes still remains unknown. Even less is known about the effects of 15-LO-1 on the expression of other genes. Because of its potential to produce reactive oxygen species and lipid hydroperoxides, 15-LO-1 m...

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“…Furthermore, it has been suggested that 15-LO-1 plays an important role in angiogenesis and carcinogenesis (Viita et al, 2008). Both angiogenesis and tumor formation in two xenograft models were inhibited in transgenic mice overexpressing 15-LO-1 in ECs (Harats et al, 2005). It has been suggested that several possible pro-versus antiangiogenesis functions are mediated by metabolites derived from 15-LO-mediated lipid oxidation (Viita et al, 2008).…”

mentioning

confidence: 99%

15-oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase That Inhibits Endothelial Cell Proliferation

et al. 2009

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The formation of 15-oxo-5,8,11,13-(Z,Z,Z,E)-eicosatetraenoic acid (15-oxo-ETE) as a product from rabbit lung 15-hydroxyprostaglandin dehydrogenase (PGDH)-mediated oxidation of 15(S)-hydroperoxy-5,8,11,13-(Z,Z,Z,E)-eicosatetraenoic acid was first reported more than 30 years ago. However, the pharmacological significance of 15-oxo-ETE formation has never been established. We have now evaluated 15-lipoxygenase (LO)-1-mediated arachidonic acid (AA) metabolism to 15-oxo-ETE in human monocytes and mouse RAW macrophages that stably express human 15-LO-1 (R15L cells). A targeted lipidomics approach was used to identify and quantify the oxidized lipids that were formed. 15-oxo-ETE was found to be a major AA-derived LO metabolite when AA was given exogenously or released from endogenous esterified lipid stores by calcium ionophore (

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Inhibition of carcinogenesis in transgenic mouse models over-expressing 15-lipoxygenase in the vascular wall under the control of murine preproendothelin-1 promoter

Cited by 36 publications

References 21 publications

Reducing the “Risk” of Chemoprevention: Defining and Targeting High Risk—2005 AACR Cancer Research and Prevention Foundation Award Lecture

Reducing the “Risk” of Chemoprevention: Defining and Targeting High Risk—2005 AACR Cancer Research and Prevention Foundation Award Lecture

15-Lipoxygenase-1 Prevents Vascular Endothelial Growth Factor A– and Placental Growth Factor–Induced Angiogenic Effects in Rabbit Skeletal Muscles via Reduction in Growth Factor mRNA Levels, NO Bioactivity, and Downregulation of VEGF Receptor 2 Expression

15-oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase That Inhibits Endothelial Cell Proliferation

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