Jefferson Scientists Detail Key Molecular Pathway And Potential Drug Targets Against Cancer, Alzheimer’s And Parkinson’s Diseases

Reporting the results of a study March 1 in the journal Nature, Emad Alnemri, Ph.D., professor of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, and his co-workers at Princeton University and the University of Pittsburgh describe a particular molecular pathway involved in apoptosis. Scientists believe apoptosis gone awry underlies neurodegenerative diseases, autoimmune diseases such as lupus, and cancer.

In the study, the researchers explain how two similar proteins compete for control of a cell’s ability to die at a preset time. The Jefferson team focused on an enzyme, caspase-9, which Dr. Alnemri’s group discovered. Caspases are cellular enzymes that bring about apoptosis. Other proteins in the cell known as inhibitors of apoptosis, or IAPs, block caspase activity, preventing cells from dying. The scientists described the relationship among caspase-9, XIAP (an IAP that inhibits caspase-9), and another protein called Smac (also known as DIABLO) that disrupts the caspase-9-XIAP interaction.

The scientists discovered how a region in the XIAP protein called BIR3 attaches to caspase-9 and blocks its activity. They also learned how Smac disrupts the caspase-XIAP interaction by competing with caspase-9 for the same docking space on the BIR3 region of XIAP.

“We showed how Smac disrupts the interaction with XIAP and caspase-9, resulting in activation of caspases and apoptosis,” says Dr. Alnemri, who is also deputy director of the Jefferson Center for Apoptosis Research and a member of Jefferson’s Kimmel Cancer Center. Harnessing Smac’s activity or devising a drug to mimic it allows caspase activation and apoptosis to occur.

“By understanding how caspase-9, XIAP and Smac interact with each other, we will be able to develop small molecules – drugs – based on these interactions to mimic them and fight cancer, neurodegenerative diseases and other diseases in which apoptosis is involved in the pathologic process,” says Dr. Alnemri. “Our study defines how XIAP blocks caspase-9 activity, a first step in designing and improving the efficacy of new drugs to inhibit or activate caspases.

“Biotech companies are actually using caspases as drug targets to prevent or activate apoptosis,” he says. “You want to activate apoptosis by activating caspases in cancer to kill the cells. In cases of neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and others such as stroke and heart attack, you want to prevent apoptosis by inhibiting caspases.”

Apoptosis is a fundamental biological process vital to cell differentiation and normal development. In human embryos, for example, apoptosis creates fingers from mitt-like hands. It occurs during normal aging and sometimes during irreversible cell injury from radiation and other poisons. Apoptosis has received a great deal of attention in the popular press in recent years when scientists discovered that part of the reason cancer cells grow with out of control is because they lose the ability to die at a preset time. In many cancers, IAP activity abounds. “You want to develop a drug that binds to IAPs in a manner similar to Smac to specifically disrupt the caspase-IAP interaction in cancer cells, activating apoptosis, killing the cancer, for example,” Dr. Alnemri explains.

One company, IDUN Pharmaceuticals in San Diego, which also supports Dr. Alnemri’s research, has already begun conducting clinical trials with synthetic compounds it developed to inhibit caspases. It is also studying their use in treating heart attacks. In a heart attack, ischemia – a lack of blood flow and oxygen to the heart – results in heart muscle cells dying. Injecting IAPs within a few hours may help prevent apoptosis and heart muscle cell death, reducing heart damage. The National Institute of Aging funded the research.