Posted November 22, 2013: by Bill Sardi

    How absurd!  Cancer researchers are saying they have conquered the “Everest of cancer genes” with the discovery of a synthetic molecule that inhibits the mutated RAS cancer-promoting gene.  The lead scientist says: ‘People have tried to drug every part of ras and looked at every nook and cranny on it and screened a million compounds and never found anything that inhibits it well.”  They say their molecule is “30 years in the making.”  Their research is published in a recent edition of SCIENCE.

    Now scroll down to read a report published in the journal NUTRITION in 1997 which cites that orange peel oil and its primary active ingredient limonene effectively block mutated RAS genes. Molecules in garlic and omega-3 fish and flaxseed oil do the same. So does resveratrol. How many are they allowing to needlessly die while they attempt to make blockbuster drugs to cure cancer?  –Bill Sardi, Knowledge of Health, Inc.


    Breakthrough in fight to overcome the deadliest cancers: Scientists find way to shut off gene that causes third of all tumours

    Find could lead to drugs for most difficult to treat cancers

    More pancreatic, bowel and lung cancers could be cured

    New treatment would have fewer unpleasant side effects


    PUBLISHED: 18:29 EST, 20 November 2013 | UPDATED: 04:40 EST, 21 November 2013

    The ‘Everest’ of cancer genes has been conquered by scientists.

    They have found a way of shutting off a gene that causes a third of all tumors, including some of the most deadly.

    Despite advances in medicine, cancer kills more than 150,000 Britons a year – the equivalent of a life every four minutes.

    The breakthrough could lead to new drugs for hard-to-treat cancers. As well as saving lives, the new treatments should have fewer side-effects than existing medicines

    The excitement surrounds a gene called ras, which when mutated can trigger the development of tumors, fuel their growth and keep them alive.

    A drug that shuts it down has eluded some of the best brains in science for more than 30 years, leading many to believe it was unbeatable.

    Now, US scientists have succeeded in making a chemical that kills ras-driven human lung cancer cells.

    Researcher Kevan Shokat, of the Howard Hughes Medical Institute at the University of California, described the rogue gene as ‘the Everest of cancer mutations’.

    He said: ‘People have tried to drug every part of ras and looked at every nook and cranny on it and screened a million compounds and never found anything that inhibits it well.

    ‘We are very excited. We believe this has real implications for patients.’ Cancers caused by the ras gene are particularly fast growing and spreading and difficult to treat.

    ‘They include many pancreatic, lung and bowel cancers, which between them kill almost 60,000 Britons a year.

    Pancreatic cancer is the most deadly common cancer, with fewer than 20 per cent of patients alive a year after diagnosis and under 4 per cent surviving for five years.

    Lung cancer kills more Britons than any other form of the disease, with almost 35,000 deaths a year. Bowel cancer is the second biggest cancer killer, with around 16,000 deaths annually.

    It is hoped that by shutting off ras, the new drug will stop the growth of tumours and shrink them.

    Crucially, it acts only on the cancer-causing form of the ras gene, meaning healthy cells are spared. This should cut the risk of side-effects such as sickness, nausea and hair loss normally seen with cancer drugs.

    Dr Shokat, who has formed a company to commercialize his work, said: ‘What is very special about this drug is that it only works in cells that have this particular mutation. That distinguishes it from every other cancer drug we know of.’

    Dr Frank McCormick, leader of a £6.2million US government initiative to tackle the ras gene, said: ‘Cancers driven by ras are the most difficult to treat.

    Dr Shokat and his team have taken a brilliantly innovative approach and have developed a strategy for targeting a mutant form of ras with exquisite specificity.’

    The new drug works against one rogue form of ras but Dr Shokat believes it should be possible also to make drugs that work against the other forms.

    His chemical has so far been tested only on cells in a dish but a new medicine could be tested on people in three years and on the market by 2021. However, it will have to be shown to be safe and effective in large-scale trials on patients.

    Dr Emma Smith, senior science information officer at Cancer Research UK, said: ‘This lab study is another step forward in finding ways to shut down an important molecule called ras, which is a key player in cancer development.

    ‘And this molecule has been notoriously difficult to block with drugs.

    ‘Ras is one of the most important molecules in cancer and when it goes wrong it can cause aggressive cancers that are hard to treat, so finding chemicals that stop it working is a vital area of research that could lead to potent new drugs in the future.’

    EDITORIAL COMMENTS Nutrition Vol. 13, No. 10, 1997

    Modulation of RAS Expression in Human Malignant Cells by Dietary Supplements

    There is substantial epidemiologic data to suggest that healthy diets, that is, those high in fruits and vegetables, decrease the risk of a variety of cancers.1 For instance, low-fat diets are associated with a decreased risk of breast and colon carcinomas.i For many dietary supplements, the precise biological mechanisms that underlie their chemopreventive activities are unknown. However, our understanding of the mechanisms underlying the anticancer activities for some dietary constituents is increasing. One example of such a constituent is limonene, which is a monoterpene that is found in a variety of citrus fruits and is a major constituent of orange peel oil. Limonene has been extensively studied in animal models as a chemoprotective* and chemotherapeutic agent.3 In particular, limonene will prevent and cause regression of mammary tumors in 7,12dimethylbenz[a]anthra- cene-treated rats.3

    Limonene’s anticarcinogenic effect has been re-famesyl pyrophosphate (FPP) and is necessary for RAS’s mito- genie activity.i3J4 FPP is a derivative of mevalonic acid and is a precursor for de novo cholesterol biosynthesis (Fig. 1). Thus there are at least four strategies for interfering with the RAS signal transduction pathway. The first strategy is depleting cells of FPP. This can be accomplished in the laboratory by blocking hy- droxymethylglutaryl coenzyme A reductase (Fig. 1, step 1).14-i6 Such inhibitors are widely used in the clinic to treat patients with hypercholesterolemia, l7 although the high concentrations neces- sary to inhibit RAS processing are rarely achieved in human plasma.i6J8Jg The second strategy is blocking famesyl protein transferase (FPTase), which is the enzyme that catalyzes linkage of farnesyl to RAS (Fig. 1, step 2). This approach is being explored by a number of investigators who have generally focused on developing new pharmaceutic peptidomimetic RAS analogs to block FPTase competitively with respect to RAS,*O-24 although some have chosen to develop FPP analogs to block FPTase competitively with respect to FPP.25 Although at least one FPTase inhibitor occurs naturally, cylindrol A,26 it probably is not found in our diets in high enough quantities to interfere with FPTase. The third strategy is decreasing RAS levels by either depressing ras gene transcription (Fig. I, step 3′) or mRNA translation (Fig. 1, step 3″). The fourth strategy is increasing RAS protein degra- dation (Fig. 1, step 4).

    The association of the RAS pathway with dietary and, in partic- ular, monoterpene preventive and therapeutic anticancer activities lies in the ability of these compounds to decrease RAS levels. The monotetpenes decrease the amount of radiolabeled mevalonic acid incorporated into immunoprecipitable RAS proteins.27 These find- ings were interpreted to indicate that the monoterpenes interfere with RAS posttranslational modification presumably at the level of FPTase. In fact, extremely high concentrations of these compounds will inhibit FPTase.** Our laboratory has verified that the monoter-Transferase, 3′-RAStranscription, 3″~RAStranslation, and 4-RAS degradation. produced by feeding animals orange peel oil rather than purified limonene.4 The effect has also been enhanced by feeding perillyl alcohol, an oxidized derivative of limonene that has demonstrated more potent antiproliferative activities against malignant cells than does limonene itself.5,6

    Parallel to the increased understanding of human dietary ef- fects on cancer prevention and treatment has been marked expan- sion in our knowledge of the molecular mechanisms for carcino- genesis. Central to the development of a large percentage of human cancers is the finding that the ras oncogene is frequently mutated to encode for abnormal RAS proteins (i.e., activated RAS) that promote excessive cell proliferation.7 Wild-type ras encodes for RAS proteins that are involved in the transduction of signals from membrane receptor-linked tyrosine kinases to intra- cellular signal transduction pathways, such as the mitogen-acti- vated protein kinase cascade.s.9 RAS normally binds to guanosine triphosphate (GTP) and catalyzes its hydrolysis to guanosine diphosphate (GDP). The RAS-GTP complex signals for increased cell proliferation, whereas RAS-GDP lacks this activity. Mutated ras genes encode for RAS proteins that lack the ability to hydro- lyze GTP to GDP and, thus, result in increased RAS-GTP levels that lead to excessive positive signaling for cell proliferation. Excessive positive signaling as well as an induced genomic insta- bility are believed to underlie the oncogenic potential of mutated ras.s-L1 Because injection of inactivating anti-RAS antibodies into proliferating cells that have been transfected to express activated ras genes results in reversion of the excessive proliferative rates associated with this transfection, I2 RAS has become an attractive target for developing novel anticancer therapies.

    RAS transmits signals from the extracellular to intracellular compartment and is normally closely localized to the inner surface of the cell membrane.8~9 This localization is promoted by covalent posttranslational modification of RAS to the famesyl moiety of penes lessen the amount of radiolabeled mevalonic acid incorporated into RAS.16,29However, we have discovered that in human malignant cells, this observation does not result from impairment of RAS processing by FPP depletion or from FPTase inhibition, but rather from decreased RAS protein synthesis (Fig. 1, step 3′ or 3″) and increased RAS protein degradation (Fig. 1, step 4).*6,29The former effect requires only low levels of monoterpenes, whereas the latter effect is observed only with high monoterpene concentrations. These findings are particularly intriguing because the lower concentrations of monoterpenes to diminish RAS synthesis can likely be safely achieved in humans.

    Currently, the National Cancer Institute is supporting early clini- cal testing of monoterpenes in patients with cancer. We have initiated a trial that will determine whether perillyl alcohol induces in humans the same molecular and biochemical changes in RAS processing that are observed in tissue culture systems in the laboratory.

    Close examination of the foods we consume has revealed many constituents that display the ability to combat RAS- linked tumorigenesis. We have shown that the monoterpenes, such as limonene and perillyl alcohol, reduce the overall amount of RAS present.i6**9 It should be noted that many other potential dietary interventions such as garlic, the omega-3 fatty acids, and green tea may influence the signal transduction pathways associated with cancers. Diallyl disulfide, an organo-sulfur compound in garlic, inhibits tumor growth in nude mice in part by blocking RAS localization to the membrane.30 The w-3 fatty acids have recently been demonstrated to interfere with RAS membrane localization in colonic tumors in diet- supplemented animals.31 Finally, although not altering RAS expression directly, the polyphenolic compounds that are found in green tea appear to exhibit chemopreventive properties by preventing the ras mutations induced by nitrosoamines and polycyclic aromatic hydrocarbons in animal models.32

    Continued investigation into this fertile research area holds hope for a clearer understanding of how attainable dietary manipulations may specifically interfere with the RAS signal transduction pathway and consequently with the development and progression of RAS-related cancers in humans.


    Departments of Internal Medicine & Pharmacology University of Iowa Iowa City, Iowa, USA


    1. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer preven- tion: a review of the epidemiological evidence. Nutr Cancer 1992;18: 1
    2. Elegbede JA, Elson CE, Qureshi A, Tanner MA, Gould MN. Inhibi- tion of DMBA-induced mammary cancer by the monoterpene d-limonene. Carcinogenesis 1984;5:661
    3. JA, Elson CE, Tanner MA, Qureshi A, Gould MN. Regres- sion of rat primary mammary tumors following dietary d-limonene. J Natl Cancer Inst 1986;76:323
    4. Maltzman TH, Hurt LM, Elson CE, Tanner MA, Gould MN. The prevention of nitrosomethylurea-induced mammary tumors by d-limonene and orange oil. Carcinogenesis 1989;10:781
    5. Crowell PL, Ren Z, Lin S, Vedejs E, Gould MN. Structure-activity relationships among monoterpene inhibitors of protein isoprenylation and cell proliferation. Biochem Pharmacol 1994;47:
    6. Haag JD, Gould MN. Mammary carcinoma regression induced by perillyl alcohol, a hydroxylated analog of limonene. Cancer Chemother Pharmacol 1994;34:477
    7. Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989;49:4682
    8. BarbacidM. RAS genes. Annu Rev B&hem 1987;56:779
    9. Lowry DR. Willumsen BM. Function and regulation of RAS. Annu Rev Biochem 1993;62:851
    10. Chang EH, Furth ME, Scolmck EM, Lowry DR. Tumorigenic transfor- mation of mammalian cells induced by a normal gene homologous to the oncogene of Harvey murine sarcoma virus. Nature 1982;297:479
    11. Denko NC, Giaccia AJ, Stringer JR, Stambrook PJ. The human Ha-ms oncogene induces genomic instability in murine fibroblasts within one cell cycle. Proc Natl Acad Sci USA 1994;91:1524
    12. Feramisco JR, Clark R, Wong G, et al. Transient reversion of ras oncogene-induced transformation by antibodies specific for amino acid 12 of ras protein. Nature 1985;314:639
    13. Hancock JF, Magee AI, Childs JE, Marshall CJ. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 1989;57:1167
    14. Schafer WR, Kim R, Steme R, et al. Genetic and pharmacologic suppression of oncogenic mutations in RAS genes of yeast and humans. Science 1989;245:379
    15. Sinensky M, Beck KA, Leonard S, Evans R. Differential effects of lovastatin on protein isoprenylation and sterol synthesis. J Biol Chem 1990;265:19937
    16. Hohl RJ, Lewis K. Differential effects of monoterpenes and lovastatin on RAS processing. J Biol Chem 1995;270: 17508
    17. Grundy SM. HMG-CoA reductase inhibitors for treatment of hyper-cholesterolemia. N Engl J Med 1988;319:24
    18. Thibault A, Samid D, Thompkins AC, et al. Phase I study of lova- statin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res 1996;2:483
    19. Hohl RJ, Lewis K, Knapp H. Plasma lovastatin bioactivity, plasma cholesterol, and mevalonic acid excretion after high dose lovastatin therapy in humans. J Investig Med 1995;43:296A
    20. Reiss Y, Goldstein JL, Seabra MC, Casey PJ, Brown MS. Inhibition of purified ~21′”” famsyl;protein transferase by CYS-AAX tetrapep- tides. Cell 1990;62:81
    21. Kohl N, Mosser S, deSohns S, et al. Selective inhibition of ra.r-dependent transfomration by a farnesyl transferase inhibitor. Science 1993;260: 1934
    22. James G, Goldstein J, Brown M, et al. Benzodiampine peptidomimetics: potent inhibitors of ras famesylation in animal cells. Science 1993;260: 1937
    23. Garcia AM, Rowe11 C, Ackerman K, Kowalczyk JJ, Lewis MD. Peptidomimetic inhibitors of ras famesylation and function in whole cells. J Biol Chem 1993;268:18415
    24. Nigan M, Seong C, Quian Y, Hamilton A, Sebti S. Potent inhibition of human tumor ~21′”” farnesyl transferase by A,A,-lacking ~21′”” CA,A,X peptidomimetics. J Biol Chem 1993;268:20695
    25. Hohl RJ, Lewis-Tibesar K, Pogatchnik DM, Weimer DF. Inhibition of RAS farnesylation by isoprenoid phosphonic acids. Clin Pharmacol Ther 1996;59: 198
    26. Singh SB, Zink DL, Bills GF, et al. Cylindrol A: a novel inhibitor of Ras farnesyl-protein transferase from Cylindrocarpon lucidurn. Tetrahedron Lett 1995;36:4935
    27. Crowell PL, Chang RR, Ren Z, Elson CE, Gould MN. Selective inhibition of isoprenylation of 21-26 kDa proteins by the anticarcino- gen d-limonene and its metabolites. J Biol Chem 1991;266:17679
    28. Gelb MH, Tamanoi F, Yokoyama K, et al. The inhibition of protein prenyltransferase by oxygenated metabolites of limonene and perillyl alcohol. Cancer Lett 1995;91:169
    29. Hohl RJ. Monoterpenes as regulators of malignant cell proliferation. Dietary pytochemicals in cancer prevention and treatment. New York Plenum Press, 1996: 137
    30. Singh SV, Mohan RR, Agarwal R, et al. Novel anti-carcinogenic activity of an organosulfide from garlic: inhibition of H-RAS oncogene transformed tumor growth in vivo by diallyl disultide is associated with inhibition of p21H-“” processing. Biochem Biophys Res Com- mun 1996;225:660
    31. Singh J, Hamid R, Reddy BS. Dietary fat and colon cancer: modulating effect of types and amount of dietary fat on ras-p21 function during promotion and progression stages of colon cancer. Cancer Res 1997;57:253
    32. Agarwal R, Mukhtar H. Cancer chemoprevention by polyphenols in green tea and artichoke. Adv Exp Med Biol 1996;410:35         PI1 SOS99-9007(97)00261-X

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