Limits...
Cytochrome P450-derived eicosanoids: the neglected pathway in cancer.

Panigrahy D, Kaipainen A, Greene ER, Huang S - Cancer Metastasis Rev. (2010)

Bottom Line: This third eicosanoid pathway consists of two main branches: ω-hydroxylases convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases convert it to epoxyeicosatrienoic acids (EETs).Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology; but, unlike prostaglandins and leukotrienes the link between cytochome P450 metabolites and cancer has received little attention.In this review, the emerging role in cancer of cytochrome P450 metabolites, notably 20-HETE and EETs, are discussed.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Program, Children's Hospital Boston, Boston, MA, USA. dipak.panigrahy@childrens.harvard.edu

ABSTRACT
Endogenously produced lipid autacoids are locally acting small molecule mediators that play a central role in the regulation of inflammation and tissue homeostasis. A well-studied group of autacoids are the products of arachidonic acid metabolism, among which the prostaglandins and leukotrienes are the best known. They are generated by two pathways controlled by the enzyme systems cyclooxygenase and lipoxygenase, respectively. However, arachidonic acid is also substrate for a third enzymatic pathway, the cytochrome P450 (CYP) system. This third eicosanoid pathway consists of two main branches: ω-hydroxylases convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases convert it to epoxyeicosatrienoic acids (EETs). This third CYP pathway was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology; but, unlike prostaglandins and leukotrienes the link between cytochome P450 metabolites and cancer has received little attention. In this review, the emerging role in cancer of cytochrome P450 metabolites, notably 20-HETE and EETs, are discussed.

Show MeSH

Related in: MedlinePlus

a, b Bioactive eicosanoids derived from the arachidonic acid cascade. Arachidonic acid is metabolized by three pathways—the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways. Schematic overview of major mediators and their metabolites (blue); enzymes (black, boxed) and biological role (green). Inhibitors (red ovals) and agonists (green ovals). HETEs Hydroxyeicosatetraenoic acids, EETs epoxyeicosatrienoic acids, CYP cytochrome P450 enzymes. MS-PPOH is a selective inhibitor of a subset of epoxygenases. HET0016 is a selective inhibitor of the ω-hydroxlase CYP4A. The sEH inhibitor (soluble epoxide hydrolase inhibitor) increases EET levels by acting as an agonist of the EET pathway. 14,15-EEZE is a putative EET receptor antagonist. PGE2 prostaglandin E2, PGI2 prostacyclin, LTA4 leukotriene A4, DHET dihydroxyeicosatrienoic acid, 20-OH PGE2 20-hydroxy-prostaglandin E2
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2962793&req=5

Fig1: a, b Bioactive eicosanoids derived from the arachidonic acid cascade. Arachidonic acid is metabolized by three pathways—the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways. Schematic overview of major mediators and their metabolites (blue); enzymes (black, boxed) and biological role (green). Inhibitors (red ovals) and agonists (green ovals). HETEs Hydroxyeicosatetraenoic acids, EETs epoxyeicosatrienoic acids, CYP cytochrome P450 enzymes. MS-PPOH is a selective inhibitor of a subset of epoxygenases. HET0016 is a selective inhibitor of the ω-hydroxlase CYP4A. The sEH inhibitor (soluble epoxide hydrolase inhibitor) increases EET levels by acting as an agonist of the EET pathway. 14,15-EEZE is a putative EET receptor antagonist. PGE2 prostaglandin E2, PGI2 prostacyclin, LTA4 leukotriene A4, DHET dihydroxyeicosatrienoic acid, 20-OH PGE2 20-hydroxy-prostaglandin E2

Mentions: Products of arachidonic acid metabolism, including prostaglandins and leukotrienes are potent mediators of inflammation [1]. These lipid mediators, collectively called eicosanoids, play critical roles in diverse physiological and pathological processes such as pulmonary fibrosis and cancer (Fig. 1). The first two pathways of arachidonic acid metabolism are controlled by the enzyme families cyclooxygenase (COX) and lipoxygenase (LOX). These enzymes are the target of approved drugs for the treatment of pain, inflammation, asthma, and allergies [2]. Both of these pathways produce prostaglandins and leukotrienes, respectively, and have been implicated in cancer [3]. However, a third eicosanoid pathway, in which cytochrome P450 (CYP) enzymes convert arachidonic acid into hydroxyeicosatetraenoic acids (HETEs) or epoxyeicosatrienoic acids (EETs), appears to have a role in tumor growth. COX- and LOX-derived eicosanoids have been intensely studied in tumor biology, while the study of cytochrome P450-derived eicosanoids has focused on inflammation, angiogenesis, and cardiovascular function rather than cancer pathways [1–6].Fig. 1


Cytochrome P450-derived eicosanoids: the neglected pathway in cancer.

Panigrahy D, Kaipainen A, Greene ER, Huang S - Cancer Metastasis Rev. (2010)

a, b Bioactive eicosanoids derived from the arachidonic acid cascade. Arachidonic acid is metabolized by three pathways—the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways. Schematic overview of major mediators and their metabolites (blue); enzymes (black, boxed) and biological role (green). Inhibitors (red ovals) and agonists (green ovals). HETEs Hydroxyeicosatetraenoic acids, EETs epoxyeicosatrienoic acids, CYP cytochrome P450 enzymes. MS-PPOH is a selective inhibitor of a subset of epoxygenases. HET0016 is a selective inhibitor of the ω-hydroxlase CYP4A. The sEH inhibitor (soluble epoxide hydrolase inhibitor) increases EET levels by acting as an agonist of the EET pathway. 14,15-EEZE is a putative EET receptor antagonist. PGE2 prostaglandin E2, PGI2 prostacyclin, LTA4 leukotriene A4, DHET dihydroxyeicosatrienoic acid, 20-OH PGE2 20-hydroxy-prostaglandin E2
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2962793&req=5

Fig1: a, b Bioactive eicosanoids derived from the arachidonic acid cascade. Arachidonic acid is metabolized by three pathways—the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways. Schematic overview of major mediators and their metabolites (blue); enzymes (black, boxed) and biological role (green). Inhibitors (red ovals) and agonists (green ovals). HETEs Hydroxyeicosatetraenoic acids, EETs epoxyeicosatrienoic acids, CYP cytochrome P450 enzymes. MS-PPOH is a selective inhibitor of a subset of epoxygenases. HET0016 is a selective inhibitor of the ω-hydroxlase CYP4A. The sEH inhibitor (soluble epoxide hydrolase inhibitor) increases EET levels by acting as an agonist of the EET pathway. 14,15-EEZE is a putative EET receptor antagonist. PGE2 prostaglandin E2, PGI2 prostacyclin, LTA4 leukotriene A4, DHET dihydroxyeicosatrienoic acid, 20-OH PGE2 20-hydroxy-prostaglandin E2
Mentions: Products of arachidonic acid metabolism, including prostaglandins and leukotrienes are potent mediators of inflammation [1]. These lipid mediators, collectively called eicosanoids, play critical roles in diverse physiological and pathological processes such as pulmonary fibrosis and cancer (Fig. 1). The first two pathways of arachidonic acid metabolism are controlled by the enzyme families cyclooxygenase (COX) and lipoxygenase (LOX). These enzymes are the target of approved drugs for the treatment of pain, inflammation, asthma, and allergies [2]. Both of these pathways produce prostaglandins and leukotrienes, respectively, and have been implicated in cancer [3]. However, a third eicosanoid pathway, in which cytochrome P450 (CYP) enzymes convert arachidonic acid into hydroxyeicosatetraenoic acids (HETEs) or epoxyeicosatrienoic acids (EETs), appears to have a role in tumor growth. COX- and LOX-derived eicosanoids have been intensely studied in tumor biology, while the study of cytochrome P450-derived eicosanoids has focused on inflammation, angiogenesis, and cardiovascular function rather than cancer pathways [1–6].Fig. 1

Bottom Line: This third eicosanoid pathway consists of two main branches: ω-hydroxylases convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases convert it to epoxyeicosatrienoic acids (EETs).Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology; but, unlike prostaglandins and leukotrienes the link between cytochome P450 metabolites and cancer has received little attention.In this review, the emerging role in cancer of cytochrome P450 metabolites, notably 20-HETE and EETs, are discussed.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Program, Children's Hospital Boston, Boston, MA, USA. dipak.panigrahy@childrens.harvard.edu

ABSTRACT
Endogenously produced lipid autacoids are locally acting small molecule mediators that play a central role in the regulation of inflammation and tissue homeostasis. A well-studied group of autacoids are the products of arachidonic acid metabolism, among which the prostaglandins and leukotrienes are the best known. They are generated by two pathways controlled by the enzyme systems cyclooxygenase and lipoxygenase, respectively. However, arachidonic acid is also substrate for a third enzymatic pathway, the cytochrome P450 (CYP) system. This third eicosanoid pathway consists of two main branches: ω-hydroxylases convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases convert it to epoxyeicosatrienoic acids (EETs). This third CYP pathway was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology; but, unlike prostaglandins and leukotrienes the link between cytochome P450 metabolites and cancer has received little attention. In this review, the emerging role in cancer of cytochrome P450 metabolites, notably 20-HETE and EETs, are discussed.

Show MeSH
Related in: MedlinePlus