Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis.
Arachidonic acid (AA) and its metabolites have recently generated a heightened interest due to growing evidence of their significant role in cancer biology. Thus, inhibitors of the AA cascade, first and foremost COX inhibitors, which have originally been of interest in the treatment of inflammatory conditions and certain types of cardiovascular disease, are now attracting attention as an arsenal against cancer. An increasing number of investigations support their role in cancer chemoprevention, although the precise molecular mechanisms that link levels of AA, and its metabolites, with cancer progression have still to be elucidated. This article provides an overview of the AA cascade and focuses on the roles of its inhibitors and their implication in cancer treatment. In particular, emphasis is placed on the inhibition of cell proliferation and neo-angiogenesis through inhibition of the enzymes COX-2, 5-LOX and CYP450. Downstream effects of inhibition of AA metabolites are analysed and the molecular mechanisms of action of a selected number of inhibitors of catalytic pathways reviewed. Lastly, the benefits of dietary omega-3 fatty acids and their mechanisms of action leading to reduced cancer risk and impeded cancer cell growth are mentioned. Finally, a proposal is put forward, suggesting a novel and integrated approach in viewing the molecular mechanisms and complex interactions responsible for the involvement of AA metabolites in carcinogenesis and the protective effects of omega-3 fatty acids in inflammation and tumour prevention.
Hyde
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Department of Chemistry and Analytical Sciences, The Open University, Walton Hall, Milton Keynes, MK5 7AS, UK.
Missailidis
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D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001241:Aspirin / Q000737:chemistry / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D015525:Fatty Acids, Omega-3; D011720:Pyrazoles; C102643:SC 558; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D051546:Cyclooxygenase 2; D001241:Aspirin