One thing you don't hear about is how aggressive many cancers are today, which was uncommon in the past, and the only scientific explanation that makes any sense inovolves AA and other unsaturated fatty acids. I will be working on this page for a while, and so I will just post a few abstracts of studies here (at the end) as write, because these items are representative of the literature in general.

I remember reading something biologist Ray Peat wrote about how in experiments from the early to mid twentieth century it was found that animals on a fat-free diet did not develop cancer. It surprised me, to say the least; not so much the experimental results but how these results have received little, if any, mainstream media coverage (at least in recent years). Now, it's possible that this is due to a lack of familiarity with the old evidence on the part of journalists too young to know and to busy to do the research, and yet there are plenty of the kinds of studies presented below (in their abstract forms) published in recent years. In one, there is the following passage:

"In conclusion, here we demonstrate that: a) breast cancer cells retain dependence on endogenous fatty acid synthesis and sensitivity to FAS inhibition in the presence of supraphysiological levels of dietary fatty acids..."

And in another one there is:

"It is well documented that arachidonic acid (AA) and its metabolites are intimately linked to cancer biology."

In that study, the point is made that AA metabolites have the direct, cancer-causing effects, while "free" AA is so toxic that it kills cells, even cancer cells, quite easily. These researchers seem to be interested only in cancer cells, so they appear to have negelected to ask themselves the simple question, "what would happen if people ate food that depleted their bodies of AA (and also omega 3 PUFAs)?" A fat-free diet is not practical, but one that rids the body's cells of AA is (and is also very tasty). Not doing this can create a "frying pan into the fire" situation, that is, if one tries to inhibit AA metabolization, worse problems and eventually "diseases" can result.

And here are some other examples of the kind of evidence now available:

Carcinogenesis. 2006 May 15; [Epub ahead of print]

Arachidonic acid induced gene expression in colon cancer cells.

Monjazeb AM, High KP, Connoy A, Hart LS, Koumenis C, Chilton FH.

Department of Cancer Biology, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157.

It is well documented that arachidonic acid (AA) and its metabolites are intimately linked to cancer biology. However, the downstream mechanism(s) that link AA levels to cancer cell proliferation remain to be elucidated. Initial experiments in the current study showed that exogenous AA and inhibitors of AA metabolism that lead to the accumulation of unesterified AA are cytotoxic to the colon cancer cell line, HCT-116. Additionally, exogenous AA and triacsin C, an inhibitor of AA acylation, induced apoptosis and related caspase-3 activity in a transcriptionally dependent manner. Gene array analysis revealed that both exogenous AA and triacsin C alter the expression of similar genes in HCT-116 cells. For example, both down-regulate several genes with well documented roles in cell survival and apoptotic resistance. Conversely, both up regulate genes encoding AP-1 transcription factors, which have known roles in inducing apoptosis, and genes which counteract ras (Erk/MAPK) growth signaling pathways. Realtime PCR and immunoblotting demonstrated that mRNA and protein levels of one of the major AP-1 transcription factors, c-Jun is markedly elevated by exogenous AA and triacsin C. Additionally the cyclooxygenase-2 inhibitor, sulindac sulfide, increase c-Jun mRNA levels. Together, these studies reveal that the generation of intracellular AA and its subsequent impact on gene expression likely represents a critical step that regulates colon cancer cell proliferation.

Free Radic Biol Med. 2006 Feb 1;40(3):364-75. Epub 2005 Nov 4.

Role of cytochrome P450 in phospholipase A2- and arachidonic acid-mediated cytotoxicity.

Caro AA, Cederbaum AI.

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, Box 1603, One Gustave L. Levy Place, New York, NY 10029, USA. [email protected]

Phospholipases A2 (PLA2) comprise a set of extracellular and intracellular enzymes that catalyze the hydrolysis of the sn-2 fatty acyl bond of phospholipids to yield fatty acids and lysophospholipids. The PLA2 reaction is the primary pathway through which arachidonic acid (AA) is released from phospholipids. PLA2s have an important role in cellular death that occurs via necrosis or apoptosis. Several reports support the hypothesis that unesterified arachidonic acid in cells is a signal for the induction of apoptosis. However, most of the biological effects of arachidonic acid are attributable to its metabolism by mainly three different groups of enzymes: cytochromes P450, cyclooxygenases, and lipoxygenases. In this review we will focus on the role of cytochrome P450 in AA metabolism and toxicity. The major pathways of arachidonic acid metabolism catalyzed by cytochrome P450 generate metabolites that are subdivided into two groups: the epoxyeicosatrienoic acids, formed by CYP epoxygenases, and the arachidonic acid derivatives that are hydroxylated at or near the omega-terminus by CYP omega-oxidases. In addition, autoxidation of AA by cytochrome P450-derived reactive oxygen species produces lipid hydroperoxides as primary oxidation products. In some cellular models of toxicity, cytochrome P450 activity exacerbates PLA2- and AA-dependent injury, mainly through the production of oxygen radicals that promote lipid peroxidation or production of metabolites that alter Ca2+ homeostasis. In contrast, in other situations, cytochrome P450 metabolism of AA is protective, mainly by lowering levels of unesterified AA and by production of metabolites that activate antiapoptotic pathways. Several lines of evidence point to the combined action of phospholipase A2 and cytochrome P450 as central in the mechanism of cellular injury in several human diseases, such as alcoholic liver disease and myocardial reperfusion injury. Inhibition of specific PLA2 and cytochrome P450 isoforms may represent novel therapeutic strategies against these diseases.

Int J Oncol. 2004 Mar;24(3):591-608.

Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB.

Menendez JA, Mehmi I, Atlas E, Colomer R, Lupu R.

Department of Medicine, Evanston Northwestern Research Institute, Evanston, IL 60201, USA.

A biologically aggressive subset of human breast cancers has been demonstrated to overexpress fatty acid synthase (FAS), the key enzyme of endogenous FA biosynthesis. This breast cancer-specific activation of FAS-dependent lipogenesis, an anabolic-energy-storage pathway of minor importance in normal cells, would render breast cancer cells more vulnerable to anti-metabolite interventions with FAS as therapeutic target. Not surprisingly, pharmacological inhibitors of FAS have been reported to produce both cytostatic and cytotoxic effects in human breast cancer cells, as well as to suppress DNA replication. However, the signal transduction pathway(s) that link FAS hyperactivity and breast cancer cell growth has been unresolved. Here, we have attempted to provide a systematic approach to assess the role of FAS signaling on the survival and proliferation of human breast cancer cells. First, we assessed the level of FAS protein in a panel of human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-453, MDA-MB-435, ZR-75B, T47-D, BT-474, and SK-Br3). FAS expression was graded from ++++ (overexpression) in SK-Br3 cells to + (very low expression) in MDA-MB-231 cells. No correlation was noted between FAS overexpression and estrogen receptor (ER) or progesterone receptor (PR) status, whereas a positive correlation was found between high levels of FAS expression and the amplification and/or overexpression of HER-2/neu oncogene. Because metabolic adaptation of breast cancer cells to the ambient fatty acid concentration may be relevant to the goal of utilizing FAS inhibition as a chemotherapeutic target, we evaluated the effect of exogenous dietary fatty acids on the cytotoxicity resulting from the inhibition of FAS activity. Pharmacological inhibition of FAS activity by the natural antibiotic cerulenin [(2S,3R)-2,3-epoxy-4-oxo-7E,10E-dodecadienamide] resulted in a dose-dependent cytotoxicity which positively paralleled the endogenous level of FAS. Supraphysiological levels of exogenous oleic acid (OA), a omega-9 monounsaturated fatty acid synthesized from a primary-end product of FAS palmitate, significantly diminished cell toxicity caused by cerulenin. Indeed, OA exposure significantly reduced FAS activity and expression by 55% in FAS-overexpressing SK-Br3 cells. omega-3 (alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid) and omega-6 (linoleic acid and arachidonic acid) polyunsaturated fatty acids (PUFAs), however, were unable to rescue breast cancer cells from cerulenin-induced cytotoxicity. Pharmacological blockade of FAS activity in FAS-overexpressing SK-Br3 cells resulted in apoptosis as determined by an enzyme-linked immunosorbent assay for histone-associated DNA fragments, and confirmed by TUNEL DNA-end labeling experiments. We further characterized signaling molecules that participate in the cellular events that follow inhibition of FAS activity and precede apoptosis in breast cancer cells. In SK-Br3 cells, cerulenin-induced inhibition of FAS activity resulted in down-regulation of p53, and up-regulation of cyclin-dependent kinase inhibitor (CDKi) p21WAF1/CIP1. Treatment with cerulenin or a novel small-molecule inhibitor of FAS C75 resulted in a dramatic accumulation of CDKi p27KIP1, which was accompanied by a noteworthy translocation of p27KIP1 from cytosol to cell nuclei. Strikingly, FAS inhibition also caused a significant activation of the Raf-mitogen-activated protein kinase (MEK) extracellular signal-regulated kinase (ERK1/2) cell survival pathway. Interestingly, we demonstrated that inhibition of FAS activity increased the nuclear-to-cytoplasmic ratio of BRCA1, a breast cancer tumor suppressor protein, as well as it induced a nuclear translocalization of the anti-apoptotic nuclear transcription factor-kappaB (NF-kappaB). In conclusion, here we demonstrate that: a) breast cancer cells retain dependence on endogenous fatty acid synthesis and sensitivity to FAS inhibition in the presence of supraphysiological levels of dietary fatty acids, supporting the notion that FAS inhibition may be useful in treFAS inhibition may be useful in treating breast cancer in vivo; b) endogenous fatty acid synthesis is functional in breast cancer cells and is vital since its pharmacological inhibition is cytotoxic by promoting apoptosis, and c) specific blockade of FAS activity induces the accumulation, activation, and/or cellular relocalization of multiple and diverse pro- and anti-apoptotic signaling pathways, suggesting that p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB play a novel role in the breast cancer cell response to a metabolic stress after perturbation of FAS-dependent de novo fatty acid biosynthesis.

Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11280-5.

Intracellular unesterified arachidonic acid signals apoptosis.

Cao Y, Pearman AT, Zimmerman GA, McIntyre TM, Prescott SM.

The Huntsman Cancer Institute, and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112, USA.

Cyclooxygenase-2 (COX-2) is up-regulated in many cancers and is a rate-limiting step in colon carcinogenesis. Nonsteroidal antiinflammatory drugs, which inhibit COX-2, prevent colon cancer and cause apoptosis. The mechanism for this response is not clear, but it might result from an accumulation of the substrate, arachidonic acid, an absence of a prostaglandin product, or diversion of the substrate into another pathway. We found that colon adenocarcinomas overexpress another arachidonic acid-utilizing enzyme, fatty acid-CoA ligase (FACL) 4, in addition to COX-2. Exogenous arachidonic acid caused apoptosis in colon cancer and other cell lines, as did triacsin C, a FACL inhibitor. In addition, indomethacin and sulindac significantly enhanced the apoptosis-inducing effect of triacsin C. These findings suggested that unesterified arachidonic acid in cells is a signal for induction of apoptosis. To test this hypothesis, we engineered cells with inducible overexpression of COX-2 and FACL4 as "sinks" for unesterified arachidonic acid. Activation of the enzymatic sinks blocked apoptosis, and the reduction of cell death was inversely correlated with the cellular level of arachidonic acid. Inhibition of the COX-2 component by nonsteroidal antiinflammatory drugs restored the apoptotic response. Cell death caused by exposure to tumor necrosis factor alpha or to calcium ionophore also was prevented by removal of unesterified arachidonic acid. We conclude that the cellular level of unesterified arachidonic acid is a general mechanism by which apoptosis is regulated and that COX-2 and FACL4 promote carcinogenesis by lowering this level.

Int J Urol. 2006 Aug;13(8):1086-91.

Inhibition of 5-lipoxygenase pathway suppresses the growth of bladder cancer cells.

Hayashi T, Nishiyama K, Shirahama T.

Many stimuli, including growth factors and cytokines, activate arachidonic acid (AA) metabolic pathways, which are involved in cancer development and progression. We examined the effects of a series of pharmacological inhibitors of AA metabolic enzymes on bladder cancer cells to determine the role of AA pathway in this malignancy. Human bladder cancer cell lines were treated with various AA metabolic enzymes inhibitors for lipoxygense (LOX) and cyclooxygenase (COX) pathways, and the growth suppression effects were examined. The enzyme expression in cancer cells was examined by immunoblot analyses. A 5-LOX-specific inhibitor, AA861, dose-dependently inhibited the growth of bladder cancer cells. The growth inhibitory effects were greatly abolished by 5-LOX product, 5-HETE, but not by other LOX products examined. They were observed in four cancer cells that expressed 5-LOX, but not in one that did not. Of a series of LOX and COX pathway inhibitors, AA861 was the strongest one to suppress the growth of cancer cells. Bladder cancer cells frequently expressed 5-LOX. A 5-LOX-specific inhibitor, AA861, revealed the strongest growth suppression of those cells compared to other LOX and COX pathway inhibitors, and the growth suppression effects were considered to be due to inhibition of the enzymatic activity. Therefore, 5-LOX may play a regulatory role in proliferation and/or survival of bladder cancer, and may be a therapeutic target for the disease.