title: Augmentation of chemotherapy-triggered glioma cell apoptosis by blockade of arachidonic acid metabolism--the potential role of ceramide accumulation.
abstract: There has been recent interest in using cyclooxygenase-2 inhibitors in an effort to increase the efficacy of chemotherapy and/or radiation for treatment of malignant brain tumors. Although the mechanism is unclear, one result may be the accumulation of arachidonic acid (AA). AA is the key substrate for several biochemical pathways involved in the inflammatory cascade, including the cyclooxygenase (COX) enzymes. Cyclooxygenase-1 and cyclooxygenase-2 metabolize AA to produce prostaglandins and thromboxanes. Levels of these enzymes and their products are upregulated in gliomas, especially in malignant tumors. Likewise, the enzyme 5-lipoxygenase, also elevated in malignant gliomas, metabolizes AA to produce leukotrienes. Alternatively, enzymes of the cytochrome p450 family can metabolize AA to various products, some of which may aid glioma growth and angiogenesis. Unmetabolized AA activates the enzyme neutral sphingomyelinase, which produces ceramide, a second messenger and potent activator of apoptosis. It is hypothesized that simultaneous blockade of the COX, lipoxygenase, and/or cytochrome p450-mediated pathways would lead to greater accumulation of intracellular AA, resulting in elevated ceramide levels, thereby priming glioma cells for treatment-induced apoptotic cell death. Manipulation of AA/bioactive lipid metabolism, using readily available, well-tolerated medications may have the potential to increase the efficacy of currently used glioma treatments.
authors.affiliation: Division of Neurosurgery, Department of Clinical Neurosciences, Foothills Medical Centre, Room C1243, 1403, 29 St. NW Calgary, Alberta, Canada T2N 2T9. domahen@ualberta.ca
authors.forename: David A
authors.initials: DA
authors.lastname: Omahen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016718:Arachidonic Acid / Q000378:metabolism; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004789:Enzyme Activation; D005910:Glioma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D058945:Lipoxygenases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D058945:Lipoxygenases; D011451:Prostaglandin-Endoperoxide Synthases; D013108:Sphingomyelin Phosphodiesterase