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Department of Biochemistry, Brandeis University, Waltham, Massachusetts, USA
1Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA. E-mail: llevine{at}brandeis.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTS AND DISCUSSIONREFERENCES |
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Key Words: AA • retinoid • COX-2 • antioxidant
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONREFERENCES |
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. Cancer preventive agents include 1) signal transduction modulators; 2) hormonal modulators; 3) anti-inflammatory agents; 4) anti-mutagen phase II enzyme inducers; and 5) antioxidants (2)
. Clearly, identification of molecular targets that lead to cancer chemoprevention would facilitate drug development (2)
. One such target is cyclooxygenase-2 (COX-2) (3)
, the induced isoform of COX-1 (4)
. This enzyme oxygenates arachidonic acid (AA) to a substrate required for prostaglandin (PG) synthesis. Chemoprevention by nonsteroidal anti-inflammatory drugs (NSAIDs) is thought to reflect inhibition of COX-2 activity, although non-COX-mediated activities of NSAIDs have also been implicated (5)
. Retinoids suppress COX-2 induced by epidermal growth factor (6)
, as do antioxidants (7
, 8)
and peroxisome proliferator-activated receptor 
(PPAR) ligands (9)
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONREFERENCES |
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. All of the compounds release AA and, with the exception of the statins, have been reported to suppress cancer (Table 1)
. Induced PGI2 production is inhibited by most of these compounds but stimulated by vitamin D3 and tamoxifen. Concentrations that stimulate AA release or affect PGI2 production varied from 5 µM (vitamin D3) to 75 µM (–)-epigallocatechin gallate. At the concentrations used, few if any changes in cell morphology compared with controls were observed by phase microscopy. Many other compounds when tested at concentrations up to 1 mM and after a 6 h incubation do not release AA (10)
. With the exception of some of the NSAIDs, which release AA as a result of COX-2 inhibition (11)
, none of these compounds has been shown to be chemopreventive.
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Rat liver cells incubated with lactacystin in the presence of 12–0-tetradecanoyl-phorbol-13-acetate (TPA) are stimulated to produce 
10- to 20-fold more PGI2 than unstimulated control cells (12)
, presumably due to increased COX-2 activity. These increases are inhibited by cycloheximide, and actinomycin. Increases in PGI2 production have been observed after incubation of rat liver cells with epidermal growth factor, transforming growth factor 
, thapsigargin, interleukin 1, or okadaic acid (13)
. Immunoblots of extracts of rat liver cells incubated with lactacystin plus TPA have failed to identify unambiguously the isoform responsible for the increase in PGI2 production. Lactacystin does induce COX-2 in mouse neuronal and embryonic rat mesencephalic cells as measured by Western and Northern blot analyses (14)
. Bovine pulmonary artery endothelial cells, bovine embryonic thoracic aorta smooth muscle cells, rat liver cells, and rat glial cells release AA during incubation with lactacystin plus TPA (15)
. The release of AA from dividing cells is higher than from confluent cells (15)
, as is the release of AA from bovine pulmonary artery endothelial cells stimulated with Ca2+ ionophore (16)
. Similar to COX-2 activity, the AA release by rat liver cells is inhibited by the transcription and translation inhibitors actinomycin and cycloheximide, respectively (15)
.
In the complex scheme of eicosanoid metabolism, AA serves as substrate for several oxygenases (COX, lipoxygenase, and cytochrome P450 epoxygenases). It also stimulates NADPH oxidase, activates PPAR receptors, affects H+, K+ and Ca2+ channel activities, regulates gene expression, inhibits Ca2+-induced Ca2+ release, inhibits cell proliferation, and induces apoptosis (17)
. Apoptosis is initiated by exogenous AA mediated by ceramide production (11)
. It is not known whether other fatty acids, especially the eicosapentaenoic (20:5, N-3) and docosahexaenoic acids (22:6, N-3), induce apoptosis. Many cancer chemopreventive agents that inhibit COX also stimulate release of AA from rat liver cells, e.g., antioxidants, celecoxib, indomethacin, GW 3475, and retinoids (10, 18 and unpublished results). Celecoxib and indomethacin also stimulate the release of AA from the rat liver cells by a COX-independent mechanism (18)
. Molecules that stimulate enzymatic de-esterification of the phospholipids are likely candidates for drug development. Several phospholipases that can be targeted have been described (19)
. Unfortunately, a drug that stimulates AA release would also increase the pool of precursor material required for synthesis of the proinflammatory oxygenase products.
Considerable tissue specificity has been observed in the ability of individual compounds to suppress cancer; e.g., tamoxifen is chemopreventive for breast cancer but not for uterine cancer. In different cells this may reflect activities of unique or favored pathways leading to apoptosis and/or release of AA. For example, retinoids inhibit the induced COX activity in rat liver and human oral squamous carcinoma cells induced by epidermal growth factor (6)
, but these same compounds stimulate COX activity in TPA-treated dog kidney cells (20)
. A more likely explanation is that apoptosis induced by release of AA is only one of several mechanisms leading to apoptosis.
Some of the AA released by the cancer chemopreventive compounds appears to result from interaction with the cell membrane; others act by genomic mechanisms to induce a phospholipase (10)
. The membrane interaction may result in the reorientation of membrane phospholipids leading to apoptosis (21)
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Several nuclear receptor agonists release AA from cells (10)
. These agents may have the potential to be cancer chemopreventive if the AA released reaches sufficiently high concentrations and is released over long periods of time. Thiazolidinediones (PPAR agonists) release AA from rat liver cells (10)
and inhibit induced PGI2 production (unpublished results). They appear to be chemopreventive for liposarcomas (22)
. The statins, including mevastatin, lovastatin, and simvastatin, stimulate release of AA from rat liver cells. They, like vitamin D3 and tamoxifen, stimulate COX activity. An epidemiological study of cancer occurrence in patients receiving long-term treatment with statins or thiazolidinediones could be informative.
I am suggesting that cellular AA release initiates apoptosis, which leads to cancer prevention. Other bioactivities of AA, e.g., channel regulation, may affect biological processes that lead to maladies such as Alzheimer’s disease.
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ACKNOWLEDGMENTS |
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Received for publication November 19, 2002. Accepted for publication January 10, 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONREFERENCES |
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ligands suppress the transcriptional activation of cyclooxygenase-2: evidence for involvement of activator protein-1 and CREB-binding proein/p300. J. Biol. Chem. 276,12440-12448 ligand troglitazone in patients with liposarcoma. Proc. Natl. Acad. Sci. USA 96,3951-3956 (PPAR-), GW7845, inhibits rat mammary carcinogenesis. Cancer Res. 59,5671-5673This article has been cited by other articles:
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  J. N.M. Ilsley, M. Nakanishi, C. Flynn, G. S. Belinsky, S. De Guise, J. N. Adib, R. T. Dobrowsky, J. V. Bonventre, and D. W. Rosenberg Cytoplasmic Phospholipase A2 Deletion Enhances Colon Tumorigenesis Cancer Res., April 1, 2005; 65(7): 2636 - 2643. [Abstract] [Full Text] [PDF]
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