Geraniol and beta-ionone inhibit proliferation, cell cycle progression, and cyclin-dependent kinase 2 activity in MCF-7 breast cancer cells independent of effects on HMG-CoA reductase activity

Biochem Pharmacol. 2004 Nov 1;68(9):1739-47. doi: 10.1016/j.bcp.2004.06.022.

Abstract

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, a precursor of cholesterol that is also required for cell proliferation. Mevalonate depletion results in a G1 phase cell cycle arrest that is mediated in part by impaired activity of cyclin-dependent kinase (CDK) 2, and decreased expression of positive regulators of G1 to S phase progression. Inhibition of mevalonate synthesis may, therefore, be a useful strategy to impair the growth of malignant cells. Plant isoprenoids, including beta-ionone and geraniol, have previously been shown to inhibit rodent mammary tumor development, and rodent and avian hepatic HMG-CoA reductase activity. We hypothesized that the putative anti-proliferative and cell cycle inhibitory effects of beta-ionone and geraniol on MCF-7 human breast cancer cells in culture are mediated by mevalonate depletion resulting from inhibition of HMG-CoA reductase activity. Flow cytometric analysis showed a G1 arrest in isoprenoid-treated MCF-7 cells, and also a G2/M arrest at higher concentrations of isoprenoids. These compounds minimally affected the growth of MCF-10F normal breast epithelial cells. Both beta-ionone and geraniol inhibited CDK 2 activity and dose-dependently decreased the expression of cyclins D1, E, and A, and CDK 2 and 4, without changing the expression of p21cip1 or p27kip1. Although both beta-ionone and geraniol also inhibited MCF-7 proliferation, only geraniol inhibited HMG-CoA reductase activity. While these effects were significantly correlated (r2=0.89, P <0.01), they were not causally related, since exogenous mevalonate did not restore growth in geraniol-inhibited cells. These findings indicate that mechanisms other than impaired mevalonate synthesis mediate the anti-proliferative and cell cycle regulatory effects of beta-ionone and geraniol in human breast cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acyclic Monoterpenes
  • Breast Neoplasms / pathology
  • CDC2-CDC28 Kinases / metabolism*
  • Cell Cycle / drug effects*
  • Cell Division / drug effects
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 2
  • Dose-Response Relationship, Drug
  • G1 Phase / drug effects
  • Gene Expression / drug effects
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / metabolism*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Norisoprenoids / pharmacology*
  • S Phase / drug effects
  • Terpenes / pharmacology*
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Acyclic Monoterpenes
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Norisoprenoids
  • Terpenes
  • beta-ionone
  • Hydroxymethylglutaryl CoA Reductases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • geraniol