Synergistic induction of apoptosis by HMG-CoA reductase inhibitor and histone deacetylases inhibitor in HeLa cells

Biochem Biophys Res Commun. 2008 Jan 11;365(2):386-92. doi: 10.1016/j.bbrc.2007.11.002. Epub 2007 Nov 9.


HMG-CoA reductase inhibitors and histone deacetylases (HDACs) inhibitors have been shown to induce apoptosis in a variety of cells, which could potentially be used as an anticancer therapy in addition to the designated applications. In the present study, we explored the possible synergistic pro-apoptotic effects and the underlying mechanisms when the two classes of inhibitors were combined. Exposure of HeLa cells to the combined treatment of mevastatin (an inhibitor of HMG-CoA reductase) and trichostatin A (TSA) (an inhibitor of HDACs) synergistically induced apoptosis. Mevastatin treatment transcriptionally and translationally up-regulated RhoA expression in the cells by negative feedback mechanism. While TSA enhanced mevastatin-induced RhoA up-regulation, more importantly, it also accelerated mevastatin-mediated depletion of membrane-bound (geranylgeranylated) RhoA. Moreover, TSA treatment down-regulated protein geranylgeranyl transferase-I (GGTase-I) beta subunit expression, which is one of the key enzymes for protein geranylgeranylation. Taken together, TSA down-regulated GGTase-I beta expression, hence enhanced the statin-induced depletion of geranylgeranylated RhoA, which could be an important mechanism for the synergistic induction of the apoptosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acyl Coenzyme A / metabolism*
  • Apoptosis / drug effects*
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / administration & dosage*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage*
  • Lovastatin / administration & dosage
  • Lovastatin / analogs & derivatives*


  • Acyl Coenzyme A
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • 3-hydroxy-3-methylglutaryl-coenzyme A
  • mevastatin
  • trichostatin A
  • Lovastatin
  • Histone Deacetylases