title: Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs.
abstract: Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer.
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, NSW 2006, Australia. Electronic address: michael.murray@sydney.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Murray
authors.affiliation: Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, NSW 2006, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Hraiki
authors.affiliation: Discipline of Pharmacy, Graduate School of Health, University of Technology, Ultimo, NSW 2007, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Bebawy
authors.affiliation: Discipline of Pharmacy, Graduate School of Health, University of Technology, Ultimo, NSW 2007, Australia.
authors.forename: Curtis
authors.initials: C
authors.lastname: Pazderka
authors.affiliation: Discipline of Pharmacy, Graduate School of Health, University of Technology, Ultimo, NSW 2007, Australia.
authors.forename: Tristan
authors.initials: T
authors.lastname: Rawling
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010743:Phospholipids / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D005227:Fatty Acids; D008055:Lipids; D010743:Phospholipids
keywords: Alkyl phospholipid; Epoxide isostere; Lipid-based anticancer agent; PUFA epoxide; Tumor apoptosis; Tumor proliferation