Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation

Nicola Ferri, Kohei Yokoyama, Martin Sadilek, Rodolfo Paoletti, Rafael Apitz-Castro, Michael H. Gelb, Alberto Corsini

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

1. Ajoene is a garlic compound with anti-platelet properties and, in addition, was shown to inhibit cholesterol biosynthesis by affecting 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and late enzymatic steps of the mevalonate (MVA) pathway. 2. MVA constitutes the precursor not only of cholesterol, but also of a number of non-sterol isoprenoids, such as farnesyl and geranylgeranyl groups. Covalent attachment of these MVA-derived isoprenoid groups (prenylation) is a required function of several proteins that regulate cell proliferation. We investigated the effect of ajoene on rat aortic smooth muscle cell proliferation as related to protein prenylation. 3. Cell counting, DNA synthesis, and cell cycle analysis showed that ajoene (1-50 μM) interfered with the progression of the G1 phase of the cell cycle, and inhibited rat SMC proliferation. 4. Similar to the HMG-CoA reductase inhibitor simvastatin, ajoene inhibited cholesterol biosynthesis. However, in contrast to simvastatin, the antiproliferative effect of ajoene was not prevented by the addition of MVA, farnesol (FOH), and geranylgeraniol (GGOH). Labelling of smooth muscle cell cellular proteins with [3H]-FOH and [3H]-GGOH was significantly inhibited by ajoene. 5. In vitro assays for protein farnesyltransferase (PFTase) and protein geranylgeranyltransferase type I (PGGTase-I) confirmed that ajoene inhibits protein prenylation. High performance liquid chromatography (HPLC) and mass spectrometry analyses also demonstrated that ajoene causes a covalent modification of the cysteine SH group of a peptide substrate for protein PGGTase-I. 6. Altogether, our results provide evidence that ajoene interferes with the protein prenylation reaction, an effect that may contribute to its inhibition of SMC proliferation.

Original languageEnglish
Pages (from-to)811-818
Number of pages8
JournalBritish Journal of Pharmacology
Volume138
Issue number5
DOIs
Publication statusPublished - Mar 2003

Fingerprint

Protein Prenylation
Garlic
Smooth Muscle Myocytes
Cell Proliferation
Mevalonic Acid
Simvastatin
Cholesterol
Terpenes
Cell Cycle
Oxidoreductases
Farnesol
Prenylation
ajoene
Proteins
G1 Phase
Cysteine
Mass Spectrometry
Blood Platelets
High Pressure Liquid Chromatography

Keywords

  • Atherosclerosis
  • Farnesol
  • Farnesyl transferase
  • Geranylgeraniol
  • Geranylgeranyl transferase
  • Isoprenoids

ASJC Scopus subject areas

  • Pharmacology

Cite this

Ferri, N., Yokoyama, K., Sadilek, M., Paoletti, R., Apitz-Castro, R., Gelb, M. H., & Corsini, A. (2003). Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation. British Journal of Pharmacology, 138(5), 811-818. https://doi.org/10.1038/sj.bjp.0705126

Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation. / Ferri, Nicola; Yokoyama, Kohei; Sadilek, Martin; Paoletti, Rodolfo; Apitz-Castro, Rafael; Gelb, Michael H.; Corsini, Alberto.

In: British Journal of Pharmacology, Vol. 138, No. 5, 03.2003, p. 811-818.

Research output: Contribution to journalArticle

Ferri, N, Yokoyama, K, Sadilek, M, Paoletti, R, Apitz-Castro, R, Gelb, MH & Corsini, A 2003, 'Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation', British Journal of Pharmacology, vol. 138, no. 5, pp. 811-818. https://doi.org/10.1038/sj.bjp.0705126
Ferri, Nicola ; Yokoyama, Kohei ; Sadilek, Martin ; Paoletti, Rodolfo ; Apitz-Castro, Rafael ; Gelb, Michael H. ; Corsini, Alberto. / Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation. In: British Journal of Pharmacology. 2003 ; Vol. 138, No. 5. pp. 811-818.
@article{81b350467cc04e94bf3fc062dac9513a,
title = "Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation",
abstract = "1. Ajoene is a garlic compound with anti-platelet properties and, in addition, was shown to inhibit cholesterol biosynthesis by affecting 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and late enzymatic steps of the mevalonate (MVA) pathway. 2. MVA constitutes the precursor not only of cholesterol, but also of a number of non-sterol isoprenoids, such as farnesyl and geranylgeranyl groups. Covalent attachment of these MVA-derived isoprenoid groups (prenylation) is a required function of several proteins that regulate cell proliferation. We investigated the effect of ajoene on rat aortic smooth muscle cell proliferation as related to protein prenylation. 3. Cell counting, DNA synthesis, and cell cycle analysis showed that ajoene (1-50 μM) interfered with the progression of the G1 phase of the cell cycle, and inhibited rat SMC proliferation. 4. Similar to the HMG-CoA reductase inhibitor simvastatin, ajoene inhibited cholesterol biosynthesis. However, in contrast to simvastatin, the antiproliferative effect of ajoene was not prevented by the addition of MVA, farnesol (FOH), and geranylgeraniol (GGOH). Labelling of smooth muscle cell cellular proteins with [3H]-FOH and [3H]-GGOH was significantly inhibited by ajoene. 5. In vitro assays for protein farnesyltransferase (PFTase) and protein geranylgeranyltransferase type I (PGGTase-I) confirmed that ajoene inhibits protein prenylation. High performance liquid chromatography (HPLC) and mass spectrometry analyses also demonstrated that ajoene causes a covalent modification of the cysteine SH group of a peptide substrate for protein PGGTase-I. 6. Altogether, our results provide evidence that ajoene interferes with the protein prenylation reaction, an effect that may contribute to its inhibition of SMC proliferation.",
keywords = "Atherosclerosis, Farnesol, Farnesyl transferase, Geranylgeraniol, Geranylgeranyl transferase, Isoprenoids",
author = "Nicola Ferri and Kohei Yokoyama and Martin Sadilek and Rodolfo Paoletti and Rafael Apitz-Castro and Gelb, {Michael H.} and Alberto Corsini",
year = "2003",
month = "3",
doi = "10.1038/sj.bjp.0705126",
language = "English",
volume = "138",
pages = "811--818",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation

AU - Ferri, Nicola

AU - Yokoyama, Kohei

AU - Sadilek, Martin

AU - Paoletti, Rodolfo

AU - Apitz-Castro, Rafael

AU - Gelb, Michael H.

AU - Corsini, Alberto

PY - 2003/3

Y1 - 2003/3

N2 - 1. Ajoene is a garlic compound with anti-platelet properties and, in addition, was shown to inhibit cholesterol biosynthesis by affecting 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and late enzymatic steps of the mevalonate (MVA) pathway. 2. MVA constitutes the precursor not only of cholesterol, but also of a number of non-sterol isoprenoids, such as farnesyl and geranylgeranyl groups. Covalent attachment of these MVA-derived isoprenoid groups (prenylation) is a required function of several proteins that regulate cell proliferation. We investigated the effect of ajoene on rat aortic smooth muscle cell proliferation as related to protein prenylation. 3. Cell counting, DNA synthesis, and cell cycle analysis showed that ajoene (1-50 μM) interfered with the progression of the G1 phase of the cell cycle, and inhibited rat SMC proliferation. 4. Similar to the HMG-CoA reductase inhibitor simvastatin, ajoene inhibited cholesterol biosynthesis. However, in contrast to simvastatin, the antiproliferative effect of ajoene was not prevented by the addition of MVA, farnesol (FOH), and geranylgeraniol (GGOH). Labelling of smooth muscle cell cellular proteins with [3H]-FOH and [3H]-GGOH was significantly inhibited by ajoene. 5. In vitro assays for protein farnesyltransferase (PFTase) and protein geranylgeranyltransferase type I (PGGTase-I) confirmed that ajoene inhibits protein prenylation. High performance liquid chromatography (HPLC) and mass spectrometry analyses also demonstrated that ajoene causes a covalent modification of the cysteine SH group of a peptide substrate for protein PGGTase-I. 6. Altogether, our results provide evidence that ajoene interferes with the protein prenylation reaction, an effect that may contribute to its inhibition of SMC proliferation.

AB - 1. Ajoene is a garlic compound with anti-platelet properties and, in addition, was shown to inhibit cholesterol biosynthesis by affecting 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and late enzymatic steps of the mevalonate (MVA) pathway. 2. MVA constitutes the precursor not only of cholesterol, but also of a number of non-sterol isoprenoids, such as farnesyl and geranylgeranyl groups. Covalent attachment of these MVA-derived isoprenoid groups (prenylation) is a required function of several proteins that regulate cell proliferation. We investigated the effect of ajoene on rat aortic smooth muscle cell proliferation as related to protein prenylation. 3. Cell counting, DNA synthesis, and cell cycle analysis showed that ajoene (1-50 μM) interfered with the progression of the G1 phase of the cell cycle, and inhibited rat SMC proliferation. 4. Similar to the HMG-CoA reductase inhibitor simvastatin, ajoene inhibited cholesterol biosynthesis. However, in contrast to simvastatin, the antiproliferative effect of ajoene was not prevented by the addition of MVA, farnesol (FOH), and geranylgeraniol (GGOH). Labelling of smooth muscle cell cellular proteins with [3H]-FOH and [3H]-GGOH was significantly inhibited by ajoene. 5. In vitro assays for protein farnesyltransferase (PFTase) and protein geranylgeranyltransferase type I (PGGTase-I) confirmed that ajoene inhibits protein prenylation. High performance liquid chromatography (HPLC) and mass spectrometry analyses also demonstrated that ajoene causes a covalent modification of the cysteine SH group of a peptide substrate for protein PGGTase-I. 6. Altogether, our results provide evidence that ajoene interferes with the protein prenylation reaction, an effect that may contribute to its inhibition of SMC proliferation.

KW - Atherosclerosis

KW - Farnesol

KW - Farnesyl transferase

KW - Geranylgeraniol

KW - Geranylgeranyl transferase

KW - Isoprenoids

UR - http://www.scopus.com/inward/record.url?scp=0037349211&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037349211&partnerID=8YFLogxK

U2 - 10.1038/sj.bjp.0705126

DO - 10.1038/sj.bjp.0705126

M3 - Article

C2 - 12642382

AN - SCOPUS:0037349211

VL - 138

SP - 811

EP - 818

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -