Selective inhibition of isoprenylation of 21-26-kDa proteins by the anticarcinogen d-limonene and its metabolites.

Crowell, Pamela L.; Chang, Ruey-Yi; Ren, Zhibin; Elson, Charles E.; Gould, Michael N.

doi:10.1016/s0021-9258(19)47425-5

Cited by 230 publications

(18 citation statements)

References 66 publications

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“…The mevalonate-derived intermediates, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, are covalently attached to the carboxy-terminal cysteine residue of the nuclear lamins 1 and members of the small G proteins. 2 This post-translational modification is essential to the membrane attachment and biological functions of these proteins that are vital to cell survival and growth.…”

Section: Introductionmentioning

confidence: 99%

Mevalonate depletion mediates the suppressive impact of geranylgeraniol on murine B16 melanoma cells

Katuru¹,

Fernandes²,

Elfakhani³

et al. 2011

Exp Biol Med (Maywood)

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The diterpene geranylgeraniol (all trans-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol) suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach and blood tumors with undefined mechanisms. We evaluated the growth-suppressive activity of geranylgeraniol in murine B16 melanoma cells. Geranylgeraniol induced dose-dependent suppression of B16 cell growth (IC(50) = 55 ± 13 µmol/L) following a 48-h incubation in 96-well plates. Cell cycle arrest at the G1 phase, manifested by a geranylgeraniol-induced increase in the G1/S ratio and decreased expression of cyclin D1 and cyclin-dependent kinase 4, apoptosis detected by Guava Nexin™ assay and fluorescence microscopy following acridine orange and ethidium bromide dual staining, and cell differentiation shown by increased alkaline phosphatase activity, contributed to the growth suppression. Murine 3T3-L1 fibroblasts were 10-fold more resistant than B16 cells to geranylgeraniol-mediated growth suppression. Geranylgeraniol at near IC(50) concentration (60 µmol/L) suppressed the mRNA level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by 50%. The impact of geranylgeraniol on B16 cell growth, cell cycle arrest and apoptosis were attenuated by supplemental mevalonate, the product of HMG-CoA reductase that is essential for cell growth. Geranylgeraniol and d-δ-tocotrienol, a down-regulator of HMG-CoA reductase, additively suppressed the growth of B16 cells. These results support our hypothesis that mevalonate depletion mediates the tumor-specific growth-suppressive impact of geranylgeraniol. Geranylgeraniol may have potential in cancer chemoprevention and/or therapy.

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Section: Introductionmentioning

confidence: 99%

Mevalonate depletion mediates the suppressive impact of geranylgeraniol on murine B16 melanoma cells

Katuru¹,

Fernandes²,

Elfakhani³

et al. 2011

Exp Biol Med (Maywood)

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“…During the course of our studies (reviewed in Refs. [34][35][36][37] we discovered that d-limonene, a cyclic monoterpene, decreased with some selectivity, the incorporation of radiolabeled mevalonolactone into 21-26-kDa proteins (154). Perillic acid, dihydroperillic acid, and limonene-1,2-diol appear in the plasma of humans following the administration of d-limonene (155).…”

mentioning

confidence: 99%

Isoprenoid-Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer

Elson

Peffley

Hentosh

et al. 1999

Experimental Biology and Medicine

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Pure and mixed isoprenoid end products of plant mevalonate metabolism trigger actions that suppress 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity. These actions modulate HMG CoA reductase mRNA translation and the proteolytic degradation of HMG CoA reductase. Such post-transcriptional events, we propose, are activated directly by acyclic isoprenoids and indirectly by cyclic isoprenoids. Isoprenoids, acting secondarily to the dominant transcriptional effector of sterologenesis, modestly lower cholesterol levels, if and only if, sterologenesis is not repressed by a saturating imput of dietary cholesterol. An anomaly associated with tumor growth-a sterol feedback-resistant HMG CoA reductase activityensures a pool of sterologenic pathway intermediates. Such intermediates provide lipophilic anchors essential for membrane attachment and biological activity of growth hormone receptors, nuclear lamins A and B, and oncogenic ras. Tumor HMG CoA reductase retains high sensitivity to the isoprenoid-mediated secondary regulation. Repression of mevalonate synthesis by plant-derived isoprenoids reduces ras and lamin B processing, arrests cells in G1, and initiates cellular apoptosis. This unique tumor cell-specific sensitivity allows isoprenoids to be used for tumor therapy, an application emulating that of the statins, but one free of adverse effects. When evaluated at levels provided by a typical diet, isoprenoids individually have no impact on cholesterol synthesis and tumor growth. Nonetheless, isoprenoid-mediated activities are additive, and, sometimes synergistic. Therefore, the combined actions of the estimated 23,000 isoprenoid constituents of plant materials, acting in concert with other chemopreventive phytochemicals, may explain the lowered cancer risk associated with a diet rich in plant products. In contrast, that lowering of cancer risk does not correspond to supplemental intake of other dietary factors associated with fruits, vegetables, and cereal grains, namely fiber, p-carotene, vitamin C, and vitamin E, and only weakly to supplemental folate.

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“…Since cancer cells are dying more slowly, therapy must be focussed on apoptosistriggering mechanisms and many of the 'beneficial' dietary factors that promote apoptosis in experimental systems. Citrus fruits are seen as beneficial and interesting; although d-limonene, a monocyclic monoterpene in the peel of the fruit also promotes apoptosis in model systems [160], it is recognised that-like the 'statins'd-limonene inhibits 3-hydroxymethylglutaryl CoA (HMG CoA) reductase [161] and thereby the synthesis of cholesterol (Fig. 4.…”

Section: Prostate Cancer: a Multifactorial Processmentioning

confidence: 99%

The Prevention of Prostate Cancer

Griffiths¹,

Prezioso

Turkes

et al.

Prostate Cancer

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From our better understanding of the natural history of prostate cancer, it is not unreasonable to believe that the disease is preventable. Prostate cancer has become a major healthcare problem worldwide, as life expectancy increases. Moreover, the cancer is slow growing, with a period of about 20-25 years from initiation to the stage when the clinically detectable phenotype can be identified. This review provides a simple overview of the endocrinology of prostate cancer and discusses some of the pharmaceutical agents that have been or are being tested to restrain, possibly arrest, the progression of this slowly growing cancer. Also discussed are many of the dietary factors that may influence the molecular or endocrine events implicated in its development. Dietary factors are considered responsible for the geographical differences in prostate cancer incidence and mortality. Since about 50% of all men worldwide, from both East and West, show evidence of microscopic cancer by 50 years of age, growth restraint would appear to be the pragmatic option to the possibility of preventing initiation.

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Selective inhibition of isoprenylation of 21-26-kDa proteins by the anticarcinogen d-limonene and its metabolites.

Cited by 230 publications

References 66 publications

Mevalonate depletion mediates the suppressive impact of geranylgeraniol on murine B16 melanoma cells

Mevalonate depletion mediates the suppressive impact of geranylgeraniol on murine B16 melanoma cells

Isoprenoid-Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer

The Prevention of Prostate Cancer

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