DUARTE, Calif., April 1, 2012 — City of Hope researchers found that when resveratrol, and similar compounds that activate a protein known as SIRT1, is used in combination with a different investigational drug that encourages cells to naturally die off, the results are significantly boosted compared to either treatment alone. The new collaborative study was presented by City of Hope researcher Anna A.G. Scuto, Ph.D., assistant research professor in the Department of Molecular Medicine, at the 2012 Annual Meeting of the American Association for Cancer Research (AACR) in Chicago.
Resveratrol is a compound found in red wine and associated with longevity. One reason for its demonstrated ability to extend the length of life is through activation of SIRT1, which leads to increased expression in the GADD45G gene, which is integral to how the body responds to environmental stresses that cause DNA damage to cells. Both SIRT1 activators, such as resveratrol, and HDAC inhibitors — compounds that interfere with the histone deacetylase enzyme — have independently demonstrated the ability to control the growth of tumors and encourage apoptosis, or natural cell death, in cancer cells.
“We focused on SIRT1 activation through three investigational agents — SRT501, SRT2183 and resveratrol,” Scuto said. ”All three agents had independent anti-cancer effects against lymphomas, but all were enhanced when used in combination with another investigational agent, the HDAC inhibitor LBH589.” Scuto worked under the guidance of senior author Richard Jove, Ph.D., Morgan and Helen Chu Director’s Chair and director of Beckman Research Institute of City of Hope.
The research team found that all of the agents worked, in part, by increasing the expression of the GADD45G gene. The gene initiates growth arrest and apoptosis in damaged cells. In cancer cells, GADD45G can be inhibited when the cancer cells signal other proteins to block GADD45G expression. Use of a SIRT1 activator and the HDAC inhibitor significantly increased GADD45G’s anti-cancer activity via inhibiting its negative regulators. Jove is a leading scientist on a protein called STAT3, which has critical role in cancer development. Scuto demonstrated for the first time that STAT3 is a potential negative regulator of GADD45G.
The team says this combination therapy approach could be a potential new strategy to effectively treat lymphomas.
Members of the research team included faculty from the Penn State Hershey Medical Center in Hershey, Penn., the Novartis Institute for Biomedical Research in Cambridge, Mass., and Sirtris in Cambridge. The study was supported by the National Cancer Institute, the Keck Foundation and the Tim Nesvig Lymphoma Fellowship and Research Fund.
