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Cancers
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Cyclooxygenase (COX) and Lipoxygenase (LOX) in the Inflammogenesis of Cancer
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Cyclooxygenase (COX) and Lipoxygenase (LOX) in the Inflammogenesis of Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 11224

Special Issue Editor

Prof. Dr. Randall E. Harris

E-Mail Website
Guest Editor
Colleges of Public Health & Medicine, The Ohio State University, Columbus, OH, USA
Interests: epidemiologic and molecular studies of cyclooxygenase; lipoxygenase; NSAIDs; roles in the inflammagenesis of cancer and chemoprevention of cancer

Special Issue Information

Dear Colleagues,

(1) We are pleased to invite you to contribute your original research article or review to a special issue of the Journal entitled “Cyclooxygenase (COX) and Lipoxygenase (LOX) in the Inflammogenesis of Cancer”.  Cohesive scientific evidence from molecular, animal, and human investigations suggests that constitutive overexpression of COX and/or LOX drives carcinogenesis, and reciprocally, that COX/LOX blockade has strong potential for chemoprevention and therapy. Essential features of carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX/LOX overexpression and the biosynthesis of inflammatory prostaglandins and leukotrienes. The totality of evidence clearly supports the supposition that carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of COX and the prostaglandin cascade or LOX and the leukotriene cascade in the “inflammogenesis of cancer”. The comprehensive nature of this special edition will make it an important reference resource for applied cancer research and provide a general basis for extended research and development on the inflammogenesis of cancer and the anti-neoplastic properties of COX/LOX inhibitors in cancer prevention and control.

(2) The aim of the special issue is to update and underscore scientific evidence from molecular, animal, and human investigations suggesting that constitutive overexpression of either COX or LOX drives carcinogenesis, and reciprocally, that COX/LOX blockade has strong potential for cancer prevention and therapy. 

(3) In this special issue of the Journal, we welcome contributions that address the impact of COX/LOX overexpression on essential molecular features of carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, immunosuppression and metastasis); as well as epidemiologic and clinical investigations of anti-inflammatory agents and their potential role in the chemoprevention and therapy of cancer. 

We look forward to receiving your contributions.

Prof. Dr. Randall E. Harris
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cyclooxygenase
  • prostaglandins
  • lipoxygenase
  • leukotrienes
  • cancer
  • Nonsteroidal Anti-Inflammatory Drugs (NSAID)
  • aromatase
  • estrogen

Published Papers (5 papers)

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Research

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14 pages, 1235 KiB  
Article
Cyclooxygenase and Lipoxygenase Gene Expression in the Inflammogenesis of Colorectal Cancer: Correlated Expression of EGFR, JAK STAT and Src Genes, and a Natural Antisense Transcript, RP11-C67.2.2
by Brian M. Kennedy and Randall E. Harris
Cancers 2023, 15(8), 2380; https://doi.org/10.3390/cancers15082380 - 20 Apr 2023
Cited by 1 | Viewed by 1471
Abstract
We examined the expression of major inflammatory genes, cyclooxygenase-1, 2 (COX1, COX2), arachidonate-5-lipoxygenase (ALOX5), and arachidonate-5-lipoxygenase activating protein (ALOX5AP) among 469 tumor specimens of colorectal cancer in The Cancer Genome Atlas (TCGA). Among 411 specimens without mutations in mismatch repair (MMR) genes, the [...] Read more.
We examined the expression of major inflammatory genes, cyclooxygenase-1, 2 (COX1, COX2), arachidonate-5-lipoxygenase (ALOX5), and arachidonate-5-lipoxygenase activating protein (ALOX5AP) among 469 tumor specimens of colorectal cancer in The Cancer Genome Atlas (TCGA). Among 411 specimens without mutations in mismatch repair (MMR) genes, the mean expression of each of the inflammatory genes ranked above the 80th percentile, and the overall mean cyclooxygenase expression (COX1+COX2) ranked in the upper 99th percentile of all genes. Similar levels were observed for 58 cases with MMR mutations. Pearson correlation coefficients exceeding r = 0.70 were observed between COX and LOX mRNA levels with genes of major cell-signaling pathways involved in tumorigenesis (Src, JAK STAT, MAPK, PI3K). We observed a novel association (r = 0.78) between ALOX5 expression and a natural antisense transcript (NAT), RP11-67C2.2, a long non-coding mRNA gene, 462 base pairs in length that is located within the terminal intron of the ALOX5 gene on chromosome 10q11.21. Tumor-promoting genes highly correlated with the expression of COX1, COX2, ALOX5 and ALOX5AP are known to increase mitogenesis, mutagenesis, angiogenesis, cell survival, immunosuppression and metastasis in the inflammogenesis of colorectal cancer. These genes and the novel NAT, RP1167C2.2 are potential molecular targets for chemoprevention and therapy of colorectal cancer. Full article
(This article belongs to the Special Issue Cyclooxygenase (COX) and Lipoxygenase (LOX) in the Inflammogenesis of Cancer)
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16 pages, 3115 KiB  
Article
Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats
by Heather N. Tinsley, Bini Mathew, Xi Chen, Yulia Y. Maxuitenko, Nan Li, Whitney M. Lowe, Jason D. Whitt, Wei Zhang, Bernard D. Gary, Adam B. Keeton, William E. Grizzle, Clinton J. Grubbs, Robert C. Reynolds and Gary A. Piazza
Cancers 2023, 15(3), 646; https://doi.org/10.3390/cancers15030646 - 20 Jan 2023
Cited by 4 | Viewed by 1959
Abstract
The nonsteroidal anti-inflammatory drug (NSAID) sulindac demonstrates attractive anticancer activity, but the toxicity resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins precludes its long-term, high dose use in the clinic for cancer prevention or treatment. While inflammation is a [...] Read more.
The nonsteroidal anti-inflammatory drug (NSAID) sulindac demonstrates attractive anticancer activity, but the toxicity resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins precludes its long-term, high dose use in the clinic for cancer prevention or treatment. While inflammation is a known tumorigenic driver, evidence suggests that sulindac’s antineoplastic activity is partially or fully independent of its COX inhibitory activity. One COX-independent target proposed for sulindac is cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) isozymes. Sulindac metabolites, i.e., sulfide and sulfone, inhibit cGMP PDE enzymatic activity at concentrations comparable with those associated with cancer cell growth inhibitory activity. Additionally, the cGMP PDE isozymes PDE5 and PDE10 are overexpressed during the early stages of carcinogenesis and appear essential for cancer cell proliferation and survival based on gene silencing experiments. Here, we describe a novel amide derivative of sulindac, sulindac sulfide amide (SSA), which was rationally designed to eliminate COX-inhibitory activity while enhancing cGMP PDE inhibitory activity. SSA was 68-fold and 10-fold less potent than sulindac sulfide (SS) in inhibiting COX-1 and COX-2, respectively, but 10-fold more potent in inhibiting growth and inducing apoptosis in breast cancer cells. The pro-apoptotic activity of SSA was associated with inhibition of cGMP PDE activity, elevation of intracellular cGMP levels, and activation of cGMP-dependent protein kinase (PKG) signaling, as well as the inhibition of β-catenin/Tcf transcriptional activity. SSA displayed promising in vivo anticancer activity, resulting in a 57% reduction in the incidence and a 62% reduction in the multiplicity of tumors in the N-methyl-N-nitrosourea (MNU)-induced model of breast carcinogenesis. These findings provide strong evidence for cGMP/PKG signaling as a target for breast cancer prevention or treatment and the COX-independent anticancer properties of sulindac. Furthermore, this study validates the approach of optimizing off-target effects by reducing the COX-inhibitory activity of sulindac for future targeted drug discovery efforts to enhance both safety and efficacy. Full article
(This article belongs to the Special Issue Cyclooxygenase (COX) and Lipoxygenase (LOX) in the Inflammogenesis of Cancer)
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Review

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16 pages, 1841 KiB  
Review
Cooperation between Prostaglandin E2 and Epidermal Growth Factor Receptor in Cancer Progression: A Dual Target for Cancer Therapy
by Federica Finetti, Lucrezia Paradisi, Clizia Bernardi, Margherita Pannini and Lorenza Trabalzini
Cancers 2023, 15(8), 2374; https://doi.org/10.3390/cancers15082374 - 19 Apr 2023
Cited by 7 | Viewed by 1859
Abstract
It is recognized that prostaglandin E2 (PGE2) is one key lipid mediator involved in chronic inflammation, and it is directly implicated in tumor development by regulating cancer cell growth and migration, apoptosis, epithelial–mesenchymal transition, angiogenesis, and immune escape. In addition, the expression of [...] Read more.
It is recognized that prostaglandin E2 (PGE2) is one key lipid mediator involved in chronic inflammation, and it is directly implicated in tumor development by regulating cancer cell growth and migration, apoptosis, epithelial–mesenchymal transition, angiogenesis, and immune escape. In addition, the expression of the enzymes involved in PGE2 synthesis, cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES1), positively correlates with tumor progression and aggressiveness, clearly indicating the crucial role of the entire pathway in cancer. Moreover, several lines of evidence suggest that the COX2/mPGES1/PGE2 inflammatory axis is involved in the modulation of epidermal growth factor receptor (EGFR) signaling to reinforce the oncogenic drive of EGFR activation. Similarly, EGFR activation promotes the induction of COX2/mPGES1 expression and PGE2 production. In this review, we describe the interplay between COX2/mPGES1/PGE2 and EGFR in cancer, and new therapeutic strategies that target this signaling pathway, to outline the importance of the modulation of the inflammatory process in cancer fighting. Full article
(This article belongs to the Special Issue Cyclooxygenase (COX) and Lipoxygenase (LOX) in the Inflammogenesis of Cancer)
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11 pages, 262 KiB  
Review
Potential Role of Non-Steroidal Anti-Inflammatory Drugs in Colorectal Cancer Chemoprevention for Inflammatory Bowel Disease: An Umbrella Review
by Peri Newman and Joshua Muscat
Cancers 2023, 15(4), 1102; https://doi.org/10.3390/cancers15041102 - 09 Feb 2023
Cited by 4 | Viewed by 1838
Abstract
Inflammatory Bowel Disease (IBD) is a category of autoimmune diseases that targets the destruction of the gastrointestinal system and includes both Crohn’s Disease and Ulcerative Colitis (UC). Patients with IBD are at a higher risk of developing colorectal cancer (CRC) throughout their lives [...] Read more.
Inflammatory Bowel Disease (IBD) is a category of autoimmune diseases that targets the destruction of the gastrointestinal system and includes both Crohn’s Disease and Ulcerative Colitis (UC). Patients with IBD are at a higher risk of developing colorectal cancer (CRC) throughout their lives due to chronically increased inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are potential chemopreventative agents that can inhibit the development of CRC in persons without IBD. However, the use of NSAIDs for CRC chemoprevention in IBD patients is further complicated by NSAIDs’ induction of damage to the bowel mucosal layer and ulcer formation. There has been a push in new research on chemopreventative properties of certain NSAIDs for IBD. The purpose of this umbrella review is to investigate the potential of low-dose NSAID compounds as chemopreventative agents for patients with IBD. This paper will also suggest future areas of research in the prevention of CRC for patients with IBD. Full article
(This article belongs to the Special Issue Cyclooxygenase (COX) and Lipoxygenase (LOX) in the Inflammogenesis of Cancer)
18 pages, 3353 KiB  
Review
Emphasis on Adipocyte Transformation: Anti-Inflammatory Agents to Prevent the Development of Cancer-Associated Adipocytes
by Heeju Na, Yaechan Song and Han-Woong Lee
Cancers 2023, 15(2), 502; https://doi.org/10.3390/cancers15020502 - 13 Jan 2023
Cited by 4 | Viewed by 3407
Abstract
Of the various cell types in the tumor microenvironment (TME), adipocytes undergo a dynamic transformation when activated by neighboring cancer cells. Although these adipocytes, known as cancer-associated adipocytes (CAAs), have been reported to play a crucial role in tumor progression, the factors that [...] Read more.
Of the various cell types in the tumor microenvironment (TME), adipocytes undergo a dynamic transformation when activated by neighboring cancer cells. Although these adipocytes, known as cancer-associated adipocytes (CAAs), have been reported to play a crucial role in tumor progression, the factors that mediate their transformation remain elusive. In this review, we discuss the hypothesis that inflammatory signals involving NF-ĸB activation can induce lipolysis and adipocyte dedifferentiation. This provides a mechanistic understanding of CAA formation and introduces the concept of preventing adipocyte transformation via anti-inflammatory agents. Indeed, epidemiological studies indicate a higher efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in obese patients with cancer, suggesting that NSAIDs can modulate the TME. Inhibition of cyclooxygenase-2 (COX-2) and prostaglandin production leads to the suppression of inflammatory signals such as NF-ĸB. Thus, we suggest the use of NSAIDs in cancer patients with metabolic disorders to prevent the transformation of TME components. Moreover, throughout this review, we attempt to expand our knowledge of CAA transformation to improve the clinical feasibility of targeting CAAs. Full article
(This article belongs to the Special Issue Cyclooxygenase (COX) and Lipoxygenase (LOX) in the Inflammogenesis of Cancer)
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