Researchers increase cell death in tumor targets

The findings resulted from laboratory experiments conducted at Cedars-Sinai Medical Center’s Maxine Dunitz Neurosurgical Institute and are based on the manipulation of a series of intricate biochemical events taking place within brain tumor cells.

Although most types of cells can be dismantled and cleared by apoptosis, some cancer cells have genes that enable them to thwart apoptosis and continue to grow unchecked, even when subjected to therapies that are designed to initiate or enhance apoptosis.

To overcome this problem, the scientists are testing the use of two drugs simultaneously: a protein called Trail (tumor necrosis factor related apoptosis inducing ligand), and a diabetes drug called pioglitazone.

Trail has been shown to cause cell death in several types of cancers, with negligible damage to normal cells. In the normal process of apoptosis, the enzymes caspase-8 and caspase-9 activate caspase-3, which initiates cell breakdown, leading to cell death.

In gliomas, however, several proteins that modulate these enzymes are overexpressed, resulting in down-regulation of enzyme activity. With caspase-3 activation blocked, apoptosis is halted and cancer cells grow uncontrolled. The researchers believe the diabetes drug limits the effects of the overexpressed proteins, reinstating the caspase activity and the process of apoptosis.

“We have described and are exploiting a biochemical pathway to make brain cancers much more sensitive to common therapeutic agents that cause a natural process of cell death called apoptosis,” said Dr John Yu, co-director of the Comprehensive Brain Tumor Program at the Institute.