Omega-3 polyunsaturated fatty acid derived lipid mediators: a comprehensive update on their application in anti-cancer drug discovery

ABSTRACT

Introduction

ω-3 Polyunsaturated fatty acids (PUFAs) have a range of health benefits, including anticancer activity, and are converted to lipid mediators that could be adapted into pharmacological strategies. However, the stability of these mediators must be improved, and they may require formulation to achieve optimal tissue concentrations.

Areas Covered

Herein, the author reviews the literature around chemical stabilization and formulation of ω-3 PUFA mediators and their application in anticancer drug discovery.

Expert opinion

Aryl-urea bioisosteres of ω-3 PUFA epoxides that killed cancer cells targeted the mitochondrion by a novel dual mechanism: as protonophoric uncouplers and as inhibitors of electron transport complex III that activated ER-stress and disrupted mitochondrial integrity. In contrast, aryl-ureas that contain electron-donating substituents prevented cancer cell migration. Thus, aryl-ureas represent a novel class of agents with tunable anticancer properties. Stabilized analogues of other ω-3 PUFA-derived mediators could also be adapted into anticancer strategies. Indeed, a cocktail of agents that simultaneously promote cell killing, inhibit metastasis and angiogenesis, and that attenuate the pro-inflammatory microenvironment is a novel future anticancer strategy. Such regimen may enhance anticancer drug efficacy, minimize the development of anticancer drug resistance and enhance outcomes.

KEYWORDS:

• Bioisosteric replacement
• endoplasmic-reticulum stress
• ω-3 17,18-epoxyeicosatetraenoic acid
• mitochondrial targeting
• ω-3 polyunsaturated fatty acids
• protonophoric uncoupler

Article highlights

• ω-3 Polyunsaturated fatty acid-derived mediators exert a range of beneficial effects against disease processes, including cancer.

• The use of these mediators in drug development is hampered by metabolic instability, low drug-like properties and poor in vivo availability.

• Medicinal chemistry strategies can be used to minimize metabolic instability.

• Synthetic strategies may also be used to improve drug-likeness.

• Nanoformulation can be used to enhance the delivery of lipid mediators and stabilized analogues for clinical application.

Abbreviations

15-PGDH, 15-hydroxyprostaglandin dehydrogenase; ω-3 17,18-EEA, ω-3 17,18-Epoxyeicosanoic acid; ω-3 17,18-EEQ; ω-3 17,18-epoxyeicosatetraenoic acid; 5,14-HEDGE, N-[20-hydroxyeicosa-5Z,14Z-dienoyl]glycine; AA, arachidonic acid; CDK, cyclin-dependent kinase; COX, cyclooxygenase; CTU, 16-{[4-chloro-3-trifluoromethyl)phenyl] carbamoyl}amino)hexadecanoic acid; CYP, cytochrome P450; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; EDP-EA, epoxydocosapentaenoic-ethanolamide; EEQ-EA, epoxyeicosatetraenoic-ethanolamide; EET, Epoxyeicosatrienoic acid; EPA, eicosapentaenoic acid; ER, endoplasmic reticulum; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LOX, lipoxygenase; LT, leukotriene; LXA₄, lipoxin A₄; PG, prostaglandin; PGI₂, Prostacyclin; PUFA, Polyunsaturated fatty acid; sEH, soluble epoxide hydrolase; SPM, specialized pro-resolving mediator; TTA, tetradecylthioacetic acid; TXA₂, thromboxane A₂.

Acknowledgments

The major contributions made by numerous collaborators and students in the development of this work are gratefully acknowledged.

Declaration of interest

The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

Support for this work was provided by the Australian National Health and Medical Research Council.