Proteasome inhibition – a highly effective treatment for multiple myeloma
Proteases are a group of enzymes that break (“proteolyze”) the long chainlike molecules of proteins into shorter fragments called peptides. Early view considered the protease essentially as a destructive enzyme involved in protein catabolism and generation of amino acids in an organism. Nevertheless, extensive scientific investigations over more than a century have established their meaningful proteolytic role in the control of multiple biological processes in all living organisms.
One of the ways proteases are activated is through the formation of large protein complexes, such as the proteasome. and compartmentalization of the proteolytic subunits. Multiple proteasome forms are usually present in a single cell type – the various forms differ in their substrate preferences as well as proteolytic products. Nevertheless, all proteasome forms are built on a common core particle (CP).
The overall architecture of the CP is defined by four coaxially stacked heteroheptameric rings of protein subunits. The proteolytic activity of the complex is due to three b subunits – beta1, beta2, and beta5 – present in each of the two inner rings. They have distinct cleavage specificities and been referred to as caspase-like, beta2 as tryptic-like while beta5 as chymotryptic-like respectively.
The highly regulated ubiquitin/proteasome pathway (UPP) is responsible for the degradation of approximately 80% of intracellular proteins. Ubiquitin is a small regulatory protein found “ubiquitously” in most tissues of eukaryotic organisms. The addition of ubiquitin to a substrate protein, ubiquitylation, marks the substrate for degradation by the proteasome.
Uncontrolled gene transcription in cancer cells leads to overproduction of proteins, particularly misfolded and mutated proteins – such malformed proteins must be degraded for cell survival. Therefore, cancer cells are heavily dependent on UPP and this makes them more vulnerable to proteosome inhibition compared to normal cells. Quite reasonably, proteasome has been considered to be a potent therapeutic target.
Carfilzomib has been developed as a second-generation proteasome inhibitor by Onyx Pharmaceuticals, now a subsidiary of Amgen. It is sold under the brand name of Kyprolis. In July 2012, carfilzomib was approved by the United States Food and Drug Administration (FDA) for the treatment of multiple myeloma.
Carfilzomib interacts effectively with b5 subunit of the constitutive proteosome (cCP) present in most normal tissues and b5i subunit of the immunoproteasome (iCP) present in antigen-presenting cells of the immune system. It does not show any effect to other proteasome subunits or non-proteasome substrates which could have been detrimental to normal cells.
Although carfilzomib has a much-improved efficacy and safety profile in comparison with bortezomib, the first FDA-approved drug for the treatment of multiple myeloma, yet it is associated with some cardiovascular toxicity and renal toxicity. These side-effects pose a challenge to the treatment of multiple myeloma requiring careful optimization of carfilzomib treatment.