Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells

Oncogene. 2006 Jan 12;25(2):176-85. doi: 10.1038/sj.onc.1209049.


The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.

Publication types

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

MeSH terms

  • Benzamides / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cellular Senescence / drug effects*
  • Enzyme Activation / drug effects*
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • Genes, ras / physiology*
  • Histone Deacetylase Inhibitors
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Naphthols / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / metabolism
  • Signal Transduction / drug effects*
  • Sirtuin 1
  • Sirtuins / antagonists & inhibitors
  • Tumor Cells, Cultured
  • Tyrosine / metabolism
  • beta-Galactosidase / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Benzamides
  • Histone Deacetylase Inhibitors
  • Naphthols
  • Plasminogen Activator Inhibitor 1
  • sirtinol
  • Tyrosine
  • Epidermal Growth Factor
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • beta-Galactosidase
  • SIRT1 protein, human
  • Sirtuin 1
  • Sirtuins