1. ¹Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
2. ²Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo, Japan
3. ³Shriners Hospital for Children, Boston, MA, USA

Correspondence: Dr M Kaneki, Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Rm 6604, Charlestown, MA 02129, USA. E-mail: mkaneki@partners.org

Received 23 June 2005; Accepted 8 July 2005; Published online 19 September 2005.

Abstract

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 -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.