An anti-cancer molecule with a back-up plan

Researchers in Saudi Arabia and Pakistan have uncovered the molecular mechanism behind the effectiveness of the anti-tumour agent, deguelin. 

Many chemotherapy drugs act by blocking cell division or otherwise damaging cells, causing the cells to activate a process of controlled death known as apoptosis. Apoptosis is an effective way for the body to remove unhealthy cells, but it needs to be carefully regulated. In healthy cells, maintenance proteins constantly destroy or disable apoptotic proteins responsible for activating the process. 

Although deguelin is known to cause apoptosis, the mechanism by which it acts is still under investigation. To understand how deguelin works, the researchers used physical simulations to predict how the drug binds to maintenance proteins. They found that deguelin blocks the docking site for the apoptotic proteins. This prevents them from becoming inactivated by the maintenance proteins and leads to apoptosis. 

The simulations showed that deguelin also binds to another group of proteins involved in controlling apoptosis, the ERK proteins. The ERKs are part of a signalling circuit that controls certain apoptotic proteins. By binding to ERK, deguelin interferes with the signalling process. As a result, the ERK-controlled apoptotic proteins aren’t marked for destruction, leaving them free to initiate apoptosis. 

To confirm these findings, the team tested the effect of disabling the ERK proteins in human cancer cell cultures.Following inactivation of ERK, they detected an increased level of the apoptotic protein it normally regulates, similar to the response to treatment with deguelin.

 Together, these results show that deguelin acts by disabling the systems controlling apoptosis. While earlier work has also shown that deguelin activates apoptosis, this study demonstrates that the drug interferes with two separate pathways controlling the process. While further research is still needed, deguelin’s dual activity may offer a more effective, robust alternative to other chemotherapy drugs.

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