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Proteasome Inhibitors for Cancer Therapy

© David Olle

What are proteasomes?

Proteasomes are enzymes with a complex structure and function. They are found abundantly in all cells, both normal and cancerous, and are responsible for the degradation of all regulatory proteins. The regulatory proteins are key to the activation or repression of many cellular processes, including cell-cycle progression, transcription, and apoptosis. Cell-cycle progression leads to cell division, which continues uncontrollably in the cancerous state. Transcription factors such as NF-KB activate genes responsible for the synthesis of proteins that promote cell adhesion, angiogenesis (blood vessel growth), and cell division. Although transcription factors perform roles in normal cells, in the cancerous state their hyperactivity leads to increased tumor growth. Apoptosis is programmed cell death, and is a mechanism that comes into play when the cell is so dysfunctional or damaged that it cannot be repaired.

How can proteasome inhibitors act as cancer treatments?

Since proteasomes can facilitate the cancerous state, they are attractive targets for new cancer drugs. Protein degradation by proteasomes is an essential cellular function, so proteasome inhibitors can lead to death of cancer cells by apoptosis. Proteasomes are abundant in normal cells, so why is it that proteasome inhibitors do not kill these cells as well as cancer cells? Cancer cells divide more rapidly, and have undergone disruptions in their normal regulatory pathways. Consequently, cancer cells are more sensitive to the effects of proteasome inhibitors, so correct dosages will protect normal cells.

Millennium Pharmaceuticals has been a pioneer in the development of protease inhibitors. Their product, Velcade (bortezomib), has been tested in clinical trial against many types of cancers. The drug binds to a specific site on the proteasome enzyme, thereby preventing the breakdown of proteins that have attached to the enzyme. Although the drug probably has multiple mechanisms of action, the inhibition of the transcription factor, NF-KB, is well known. Proteasome can activate NF-KB by breaking down an inhibitor protein of the transcription factor, leading to the formation of tumor promoting factors.

Clinical trials with the proteasome inhibitor

Clinical trials with bortezomib generally involve patients with advanced stages of cancer. Most patients have become non-responsive to treatments with standard drugs. The trials generally involve treatment with bortezomib and standard treatments singly and in combination. The treatments in combination often show a synergistic effect, that is, the clinical responses to the drugs in combination is greater than the effect of either drug alone.

Multiple myeloma - this disease is characterized by an abnormal proliferation of plasma cells in the bone marrow, and is invariably fatal. A phase II trial known as Summit involved treating patients who had largely become non-responsive to other standard treatments. Patients who did not respond to bortezomib were permitted to receive dexamethazone (a standard treatment) in combination. The results indicated that 35% of patients responded to bortezomib alone, while an additional 17% responded to the combination with dexamethazone. The patients responded to the treatments for an average of 12 months.