City of Hope scientists found that combining resveratrol and similar compounds together with a new investigational drug can battle cancer better than using either of the compounds alone.

Anna Scuto presented lymphoma findings at the Annual Meeting of the American Association for Cancer Research. (Photo by Darrin S. Joy)

The collaborative lab study was presented by Anna A.G. Scuto, Ph.D., assistant research professor of molecular medicine, at the 2012 Annual Meeting of the American Association for Cancer Research in Chicago.

Resveratrol is a compound found in red wine and is associated with longevity. One reason scientists say it may extend lifespan is because it activates the gene sirtuin 1, or SIRT1, which leads to increased expression in the GADD45G gene. This latter gene is integral to how the body responds to environmental stresses that cause DNA damage to cells.

Scientists are investigating both SIRT1 activators, such as resveratrol, and other drugs called histone deacetylase (HDAC) inhibitors against cancer. They have shown that both of these types of drugs can control the growth of tumors and encourage apoptosis, or natural cell death, in cancer cells.

Working 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, Scuto and her colleagues wanted to understand how several SIRT1 activators and an HDAC inhibitor would interact with the GADD45G gene — and how they would affect cancer.

“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.”

LBH589 is also known as panobinostat.

The research team found that all of the agents worked, in part, by increasing the expression of the GADD45G gene. The gene arrests growth and initiates apoptosis in damaged cells.

Cancer cells actually can inhibit GADD45G by signaling proteins to block GADD45G expression. But combining a SIRT1 activator and an HDAC inhibitor lifted the blockade on GADD45G — significantly increasing the gene’s anti-cancer activity.

Scuto also demonstrated for the first time that the gene called signal transducer and activator of transcription 3, or STAT3, is a potential negative regulator of GADD45G. Jove is a leading expert on STAT3, which plays a critical role in the development of many cancers.

The team believes this combination therapy approach could be a potential new strategy to treat lymphoma.

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.