February 10, 2003 | Proteasome inhibitors, such as Millennium’s Velcade, represent a new class of drugs that may prove effective in fighting a wide range of cancers. They work by curbing a protein regulation pathway that is kicked into overdrive in cancerous cells.
Proteasomes are part of the proteasome-ubiquitin pathway, in which many regulatory proteins -- along with many incorrectly translated proteins -- are broken down and recycled. Proteins targeted for destruction are “tagged” with ubiquitin (a small protein). The proteasomes (barrel-shaped enzyme complexes) recognize these tagged proteins, draw them inside, cut them into many pieces, and release the fragments. Some of the fragments, in turn, spur renewed production of depleted proteins.
Proper functioning of this pathway is critical to ensuring that cells proceed through a normal cycle of growth, division or programmed death (apoptosis) depending on its type of cell.
In cancer cells, the proteasome-ubiquitin pathway goes haywire. Many more proteins than usual are tagged by ubiquitin and destroyed. The decrease in regulatory proteins disrupts orderly control of the cell cycle. Roughly speaking, the cell responds by boosting production of proteins that stimulate cell survival, growth, and division, while suppressing those factors that facilitate apoptosis.
Proteasome inhibitors block the entry of proteins to proteasomes shutting down the pathway. It’s thought that the buildup of many different regulatory proteins in the cell confuses it, permitting or prompting programmed cell death. Even normal cells die after prolonged proteasome inhibition, but cancer cells have been shown to be more vulnerable.
Given the broad nature of proteasome inhibition, hopes are rising that this class of drugs may be effective against many cancers. So far, most attention has focused on Velcade’s prospects for treating multiple myeloma, but other possible targets cited by Millennium include colon, prostate, ovarian, and lung cancer. A potential problem for proteasome inhibition is that it has been implicated as a factor in brain-wasting diseases, such as mad cow. However, Velcade does not cross the blood-brain barrier, and Millennium has so far reported no evidence of risk. —John Russell
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