All eukaryotic cells contain protein complexes called proteasomes. Proteasomes maintain the concentration of proteins in cells as well as disposing of unneeded or damage proteins.
The process of degrading unwanted proteins is called proteolysis and the enzymes that carry out this process are called proteases. The degradation process produces short chains of amino acids called peptides that can be recycled and used to form new proteins.
The proteins that need to be degraded are tagged with a small protein called ubiquitin and the enzymes responsible for this tagging are called ubiquitin ligases. The protein tagged with ubiquitins is referred to as a polyubiquitin chain and this is bound by the proteasome for degradation. This overall process of protein degradation is termed the ubiquitin– proteasome pathway (UPP).
More than 80% of the proteins within the cells are degraded through this pathway, including the proteins used for cell function apoptosis, transcription, DNA repair and antigen presentation. Defects in the ubiquitin–proteasome pathway can lead to the uncontrolled and abnormal divisions of cells which can lead to cancer.
Proteasome inhibitors are drugs that were initially designed to explore the activities of proteasomes. However, once the ubiquitin–proteasome pathway was discovered, the potential effects of proteasome inhibitors as an anticancer therapy as well as for the treatment of other diseases were investigated. Studies showed that these agents could induce programmed cell death in leukaemia cell lines, Burkitt’s lymphoma and in other blood cancers and solid tumours. Studies have also shown that cancer cells are more susceptible to being killed by proteasome inhibitors than normal cells are.
The proteasome inhibitors are a relatively new class of targeted cancer therapy. One example is bortezomib which binds to and inhibits the proteasome in myeloma cells causing them to die off. Bortezomib works by activating two upstream NFκB activating kinases (RIP2 and IKKβ) and causes non-proteasomal degradation of IκB and stimulates NFκB DNA binding.
A protein called p53 is a tumour suppressor that regulates apoptosis induced by DNA damage and also regulates the transformation of oncogenes or cancer causing genes. In cancer cells, p53 is inactivated and this leads to progression of the tumor and its resistance to anti-cancer drugs. However, the activity of p53 is regulated by proteasomal degradation and proteasome inhibition can therefore increase the concentration of p53 in cells. Proteasome inhibitors have been shown to increase apoptosis in renal cell carcinoma, colon cancer, melanoma and multiple myeloma.
Carfilzomib is another example of a proteasome inhibitor and is currently undergoing clinical trials to investigate its potential as a therapy in patients with multiple myeloma and solid tumors.