Tumor-Associated Down-Regulation of 15-Lipoxygenase-1 Is Reversed by Celecoxib in Colorectal Cancer

Heslin, Martin J.; Hawkins, Ashley M; Boedefeld, William; Arnoletti, J. Pablo; Frolov, Andrey; Soong, Richie; Urist, Marshall M.; Bland, Kirby I.

doi:10.1097/01.sla.0000164177.95620.c1

Cited by 44 publications

(59 citation statements)

References 17 publications

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“…NSAIDs induce 15-LOX-1 in association with apoptosis induction, even in systems involving non-COX-2-inhibiting NSAIDs and non-COX-2-expressing colorectal cancer cells (101). These NSAID/15-LOX-1 findings have been confirmed by two other groups in colorectal cancer (102,103) and have been extended to other cancers, including esophageal (104) and gastric (105) cancer. 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).…”

Section: Molecular Targeting and The Risk Of Cancer Preventionsupporting

confidence: 64%

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 Preventionsupporting

confidence: 64%

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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“…15-LOX-1/-2 is downregulated in human colorectal tumors (118), and administration of 15-LOX-1 has shown anticarcinogenic effects (28). H. pylori induce 5-LOX-derived LT production in human gastric epithelial cells (GEC) contributing to the neutrophil infiltration characteristic of the inflammation associated with infection (104 1 O 2 is not a free radical, but has properties similar to ROS due to its electronic structure.…”

Section: Phoxmentioning

confidence: 99%

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

Bhattacharyya

Chattopadhyay

Mitra

et al. 2014

Physiological Reviews

1,896

1,258

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Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.

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“…lymphomas, lung, prostate and cervix cancers [72,73] . In keeping with this, demethylation of DNA in some cell lines was shown to increase 15-LOX-1 expression in a study by Heslin et al [39] . However, in colon cancer cell lines, conflicting data have emerged, when 5-aza-2-deoxycytidine (5-aza-dc), a hypomethylating agent, was shown to increase15-LOX-1 expression in some publications [62] and failed to induce the same in others [63] .…”

Section: Dna Methyltransferase and Promoter Site Methylationmentioning

confidence: 73%

“…Yuri et al [38] have reported down-regulation of 15-LOX-1 in colorectal adenomas. Heslin et al [39] established a positive relationship between 15-LOX-1 expression and survival in stage IV (TNM staging) colorectal cancer patients. In separate studies, 13-S-HODE added to the growth medium was found to induce apoptosis in RKO (COX-2-positive), Caco-2 (COX-2-positive), DLD1 (COX-2-negative) and SW480 colorectal cancer cells [23,24,37,40] .…”

Section: Anti-carcinogenic Roles Of 15-lox-1 In Colon Cancermentioning

confidence: 99%

“…Celecoxib, a selective COX-2 inhibitor, was found to increase 15-LOX-1 expression and thus induce apoptosis in colorectal cancer cell lines (HT-29 and DLD-1 with relatively high and low COX-2 expression, respectively) [39] . 15-LOX-1 is thus considered to be an important molecular target for the COX-2-independent NSAID-induced apoptosis in colorectal cancer cells [19,31] , but questions remained regarding the exact mechanism by which NSAIDs induced an increase in the activity of 15-LOX-1 and apoptosis.…”

Section: -Lox-1 In Apoptosis and Terminal Cell Differentiationmentioning

confidence: 99%

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15-Lipoxygenase-1 in Colorectal Cancer: A Review

Bhattacharya¹,

Mathew²,

Jayne³

et al. 2009

Tumor Biol

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Objective: Enzymes involved in the oxidative metabolism of n-6 polyunsaturated fatty acids, like lipoxygenase (LOX) and cyclooxygenase (COX), are significant in the pathogenesis of colorectal cancer. Of these enzymes, 15-LOX-1 is expressed in colon. Aim of this article is to describe the role and regulation of 15-LOX-1 in colorectal cancer and highlight its importance in cancer therapeutics. Methods: For our electronic literature research in PubMed and MEDLINE, key words related to 15-LOX-1 and colorectal cancer were used to find articles for this review. Results: From the evidences, we believe that 15-LOX-1 has anti-carcinogenic effects in colorectal cancer, dependent or independent of its metabolites, and is manifested through downstream pathways involving cGMP, PPAR, p53, p21 and NAG-1, increasing apoptosis and decreasing proliferation in cancer cells. Regulation of 15-LOX-1 expression is achieved at transcription level by global histone acetylation and may also be dependent on GATA-6, IL-4 and IL-13. Positive relationship exists between 15-LOX-1 and survival in colorectal cancer. Conclusion: Evidences strongly support that therapeutic modulation of 15-LOX-1 may be a key to the treatment of colorectal cancer. However, it is still undecided whether the up-regulation of 15-LOX-1 alone can be sufficient to treat colorectal cancer and further studies are awaited.

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Tumor-Associated Down-Regulation of 15-Lipoxygenase-1 Is Reversed by Celecoxib in Colorectal Cancer

Cited by 44 publications

References 17 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

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

15-Lipoxygenase-1 in Colorectal Cancer: A Review

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