New research from the Manchester Collaborative Centre for Inflammatory Research in the UK explains why the cancer drug Rituximab is so effective at killing cancerous cells.
Rituximab is a drug widely used in treatments of diseases where an excess of B white blood cells is produced, such as in many blood cell cancers and in autoimmune diseases like rheumatoid arthritis. Rituximab acts by triggering the destruction of B cells by forcing them to commit suicide, or by recruiting so-called natural killer white blood cells to destroy them. Despite the efficacy of this important drug, it is not understood how it works.
In a new study published in the journal Blood, Dr Daniel Davis and his research team used laser microscope imaging techniques to see how Rituximab destroyed B cells in real time. They found that Rituximab attaches to one end of the cells forming a sort of 'cap' that attracts and grabs a number of proteins. This cluster of proteins triggers a change in the shape of the cells, which go from being roundish to having a 'top and bottom' orientation. Dr Davis and colleagues asked whether this dramatic cell shape change is important for the efficacy of Rituximab in killing B cells.
By making movies under the microscope and using fluorescent markers, the researchers discovered that killer white blood cells were able to zoom in and do their job with a Rituximab-induced protein cap in place. The killer cells have about 40% efficiency on a non-capped cell (no Rituximab). However, with the drug causing the proteins to form a cluster on the one side of the cell, the efficiency of the killer cells shot up to 60%. This shows that Rituximab works by increasing the effectiveness of killer cells in eliminating B cells.
The authors of the study propose that Rituximab reorganizes the distribution of some proteins in B cells to provide more surface area on one side. Think of this as getting out of the shower and stepping onto a slippery floor or stepping on to a soft bathmat. You have greater stability of staying upright on the bathmat. Rituximab may give the killer cells something to hang on to (like a bathmat) and do their job.
Dr Davis's team was very surprised by their findings. Had it not been for the movies, they would not have been able to unravel the mystery of how the drug actually works. Dr David says:
"What our finding demonstrate is that this ability to polarize a cell by moving proteins within it should be taken into consideration when new antibodies are being tested as potential treatments for cancer cells. It appears that they can be up to twice as effective if they bind to a cell and reorganize it."