Inhibition of ubiquinone and cholesterol synthesis by the monoterpene perillyl alcohol

Ren, Zhibin; Gould, Michael N.

doi:10.1016/0304-3835(94)90396-4

Cited by 55 publications

(30 citation statements)

References 16 publications

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“…POH inhibits a distal step in the mevalonate biosynthesis pathway while lovastatin is an inhibitor of HMG-CoA reductase, which converts HMG-CoA to mevalonate in the first step of the pathway. 61,62 Thus, it is not surprising that like POH, lovastatin also induced apoptosis and an accumulation of Bcr/Abl-transformed FDC.P1 cells in G0/G1. TPA also protected the cells from lovastatin-induced cytotoxicity in that 74% of the cells treated with both lovastatin and TPA (Table 2) were viable, compared to only 19% of the cells treated with lovastatin alone.…”

Section: Figurementioning

confidence: 99%

Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest

et al. 2002

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In hematopoietic cells, the Bcr/Abl tyrosine kinase that is encoded by the Philadelphia chromosome translocation both stimulates proliferation and activates an anti-apoptotic program that is associated with a G2/M delay upon exposure to various apoptotic stimuli. We recently reported that the monocyclic monoterpene, perillyl alcohol (POH) selectively induces in Bcr/Abl transformed cells, G0/G1 arrest and apoptosis. Therefore, POH activates anti-proliferative and apoptotic pathways against which the Bcr/Abl kinase does not protect. In this report, we show that in Bcr/Abl-transformed cells, POH induces cytoplasmic acidification, redistribution of phosphatidylserine in the plasma membrane along with DNA fragmentation, all of which can be prevented by the phorbol ester, TPA. The ability of TPA to protect against POH-induced cytotoxicity was blocked by inhibitors of protein kinase C (PKC) and the Na + /H + antiport. In contrast, TPA does not protect the cells from POHmediated G0/G1 arrest. While POH inhibits a distal step in the mevalonate biosynthesis pathway, lovastatin, also a potential anticancer agent, inhibits the initial step in this pathway. Not surprisingly, lovastatin also induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed cells, however, TPA protects cells from both apoptosis and G0/G1 arrest caused by lovastatin. Thus, in Bcr/Abl-transformed cells, POH and lovastatin cause growth arrest by different mechanisms. Together, these observations demonstrate that POH-mediated cell cycle arrest precedes apoptosis and raises the possibility that that the primary effect of POH is to induce G0/G1 arrest with apoptosis being a consequence of the growth arrest. Leukemia (2002) 16, 213-222.

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Section: Figurementioning

confidence: 99%

Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest

et al. 2002

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“…Monoterpenes inhibit mevalonate metabolism and can selectively prevent the prenylation of small GTP binding proteins, including ras. 14,18,19 Reduced synthesis of both geranylgeranylated and farnesylated proteins has been observed. 19,30 Monoterpenes also upregulate the mannose-6-phosphate/insulin-like growth factor II receptor, transforming growth factor β (TGF-β), and TGF-β receptors.…”

Section: Discussionmentioning

confidence: 99%

“…The chemopreventative effects may be related to induction of phase I and phase II enzymes resulting in carcinogen detoxification 15,16 antiproliferative and/or pro-apoptotic activity, or may be due to induction of differentiation. 7,9,12,17 Additional effects that may contribute to activity against established tumors include selective inhibition of prenylation of small GTP-binding proteins, 14,18,19 modulation of other signal transduction pathways, 12,20 or cell cycle blockade. 13,21 Monoterpenes also alter mevalonate metabolism and some of these effects may contribute to the antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

“…22 Limonene reduces cholesterol biosynthesis through inhibition of 3-hydoxyl-3-methylglutaryl (HMG) coA reductase, 23 whereas perillyl alcohol affects a target further downstream. 18 Monoterpenes exhibit a high degree of oral bioavailability in mammals. 24 Limonene is rapidly oxygenated to perillic acid and dihydroperillic acid, and these active metabolites are detectable in plasma within 20 minutes following administration by gavage in rodents.…”

Section: Introductionmentioning

confidence: 99%

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Phase I Study of Perillyl Alcohol in Patients with Refractory Malignancies

Murren¹,

Pizzorno²,

DiStasio³

et al. 2002

Cancer Biology & Therapy

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We treated 21 patients in a dose-finding and pharmacokinetic study of the monoterpene perillyl alcohol with the drug given orally in 3 divided doses on a chronic basis. The average number of days that patients remained on study was 48 (range 11-172). Fatigue and low-grade nausea were dose limiting. Using this schedule, a starting dose of 1.6 g/m2 with escalation to 2.1 g/m2 as tolerated is recommended. Two major metabolites were detectable and the mean peak plasma concentrations were 383 µM for perillic acid and 27 µM for dihydroperillic acid. The peak plasma concentration and the metabolite half-life were 2h and 1h post ingestion for perillic acid, and 4 h and 2.4 h for dihydroperillic acid, respectively. Stabilization of disease was observed in one of the 16 patients evaluable for response. Many of the gastrointestinal side effects that were poorly tolerated on a chronic basis may be partly related to the soybean oil base used in the current formulation. Further development of perillyl alcohol on this schedule would be facilitated by reformulation of the capsule.

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“…These terpenes have only minor activities at central early parts of this pathway (MN Gould and Z Ren, unpublished data). However, they inhibit the isoprenylation of certain proteins (10), the synthesis of ubiquinone (Co-Q), and the conversion of lathesterol to cholesterol (11). The latter two activities have the potential to modify both cell structure and cell energy production.…”

Section: Cellular and Molecular Activitiesmentioning

confidence: 99%

Cancer Chemoprevention and Therapy by Monoterpenes

Gould¹

1997

Environmental Health Perspectives

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Monoterpenes are found in the essential oils of many plants including fruits, vegetables, and herbs. They prevent the carcinogenesis process at both the initiation and promotion/progression stages. In addition, monoterpenes are effective in treating early and advanced cancers. Monoterpenes such as limonene and perillyl alcohol have been shown to prevent mammary, liver, lung, and other cancers. These compounds have also been used to treat a variety of rodent cancers, including breast and pancreatic carcinomas. In addition, in vitro data suggest that they may be effective in treating neuroblastomas and leukemias. Both limonene and perillyl alcohol are currently being evaluated in phase clinical trials in advanced cancer patients. The monoterpenes have several cellular and molecular activities that could potentially underlie their positive therapeutic index. The monoterpenes inhibit the isoprenylation of small G proteins. Such inhibitions could alter signal transduction and result in altered gene expression. The results of a new gene expression screen-subtractive display-have identified or confirmed several up-or downregulated genes in regressing mammary carcinomas. For example, these regressing tumors overexpress the mannose 6-phosphate/IGF 11 receptor. The product of this gene both degrades the mammary tumor mitogen IGF 11 and activates the cytostatic factor TGF-f. These and other alterations in the gene expression of mammary carcinomas lead to a G1 cell cycle block, followed by apoptosis, redifferentiation, and finally complete tumor regression in which tumor parenchyma is replaced by stromal elements. It is likely that monoterpenes prevent mammary cancer during their progression stage by mechanisms similar to those that occur during therapy. In contrast, prevention of mammary cancer by polycyclic hydrocarbons such as 7,12-dimethylbenzlalanthracene occur by the induction of detoxifying phase 11 hepatic enzymes.-Environ Health Perspect 1 05(Suppl 4): 977-979 (1997)

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Inhibition of ubiquinone and cholesterol synthesis by the monoterpene perillyl alcohol

Cited by 55 publications

References 16 publications

Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest

Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest

Phase I Study of Perillyl Alcohol in Patients with Refractory Malignancies

Cancer Chemoprevention and Therapy by Monoterpenes

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