Smac-down for apoptosis

Scientists at La Trobe University have discovered how a new drug that targets proteins that inhibit the normal process of apoptosis kills cancer cells.

A research team led by Dr John Silke and Professor David Vaux has discovered that a new drug targets a cell death inhibitor protein (cIAP1) and can cure laboratory mice bearing human cell cancers.

The research is a culmination of a decade of basic research into inhibitor of apoptosis proteins (IAPs), which were first found in viruses that infect the cells of caterpillars. The viruses carry genes for IAPs to stop the caterpillar's cells from killing themselves, giving the viruses more time to replicate.

Vaux's laboratory showed that these insect viral IAPs can also inhibit the death of human cells. This led the researchers to identify similar IAP genes in mice and humans.

They later discovered an inhibitor of the IAPs - a protein known as 'Smac' or 'Diablo' - which can effectively neutralise the IAPs, causing the cells die.

As abnormally high levels of IAPs have been found in several types of human cancers, this suggested that cells in these cancers might depend on IAPs for their survival.

Based on this research, US company TetraLogic Pharmaceuticals produced a drug that mimics Smac to inhibit IAPs in cancer cells.

Together with the team at La Trobe, they have now shown that this 'smac-mimetic' IAP antagonist drug targets cIAP1, leading to production of the tumour necrosis factor cytokine that kills the tumour cells.

The latest findings were published today Cell, along with a another research paper from Genentech, which has dependently developed another IAP-antagonist drug, and commenced testing it in Phase I human clinical trials.

"Although we won't know if these new drugs will work in humans until the clinical trials have been completed, they illustrate a much more intelligent approach to combating cancer - by identifying the genes that cause cells to become cancerous, and then developing drugs to specifically target those genes to kill the cancer cells," Silke said.

Vaux said the results show how investment in basic research - "in something as obscure as insect viruses" - can potentially lead to important new treatments for human diseases. "They also reveal the global nature of collaboration in medical research."

Source: La Trobe University