Newswise — July 25, 2011 (Philadelphia, PA) –Researchers from the lab of Antonio Giordano, M.D., Ph.D., the Founder and Director of the Sbarro Institute for Cancer Research and Molecular Medicine, have identified new potential anti-tumor agents that might be effective in treating mesothelioma, one of the deadliest cancer tumors.
Scientists tested new pyrazolo [3,4-d ]pyrimidine derivative inhibitors of the SRC kinase, a well-established molecular target in cancer therapy. They found that these SRC inhibitors effectively induced cell death, through apoptosis, in mesothelioma cell lines without affecting the normal mesothelial cells, thus supporting a possible use of these agents as a safe treatment for mesothelioma.
Their findings appear in the journal Oncogene.
Interestingly, the researchers also found that the SRC inhibitors induced cell death was accompanied by an increase in the nuclear stability of the cyclin-dependent kinase inhibitor p27. This is “particularly intriguing considering that the loss of nuclear p27 expression is a well established adverse prognostic factor in mesothelioma and p27 nuclear localization is crucial for its tumor suppressive function.” said the leading author of the study, Paola Indovina, Ph.D. of the University of Siena and assistant Professor at the Sbarro Institute.
“We think that these data represent a timely contribution and suggest that p27 status should be carefully analyzed when evaluating the use of kinase inhibitors affecting SRC in clinical trials for patients with mesothelioma,” said the corresponding author of the study Francesca Pentimalli, Ph.D. of the National Cancer Institute- “Pascale Foundation” – CROM- Cancer Research Center of Mercogliano in Avellino, Italy and assistant Professor at the Sbarro Institute.
“The findings support SRC as a critical therapeutic target in mesothelioma and reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in mesothelioma cell lines, providing a new rationale for the use of SRC inhibitors in mesothelioma therapy,” says Prof. Antonio Giordano, another lead author. “It also shows that in this context, p27 is required to induce apoptosis in mesothelioma cell lines and, although this mechanism still needs to be precisely dissected, it adds further evidence supporting an active role for p27 in mediating apoptosis.”
The study was done in collaboration with Maurizio Botta full Professor of Medicinal Chemistry and Dean of the Faculty of Pharmacy, University of Siena, also adjunct Professor at the Sbarro Institute, who developed these new SRC inhibitors along with Prof. Silvia Schenone of the University of Genoa, Genoa, Italy.