Bortezomib in lymphomas

An increasing number of novel therapies are changing the landscape in oncology – the majority of which are novel biologicals with distinct mechanism from conventional cytotoxics. In the last decades, the discovery of the ubiquitin-proteasome pathway in eukaryotic organisms has revolutionized the understanding of cellular processes indispensable for protein-homeostasis through proteolysis, until then solely attributed to the lysosomal complex. The central 700 kDa protein complex, the 20S proteasome, represents its proteolytically active part.1 Substrates include abnormal or misfolded proteins (more abundant in cancer cells) and proteins with short half-life (1/3 of proteins made at any given time have a half-life <10 mn most of which are involved in key functions (cell division, apoptosis, DNA repair). Protein degradation initially felt to be a non-specific dead-end process is actually a very complex and regulated process critical for cell survival and adaptation. Almost all intracellular protein degradation occurs within the proteasome, a large multi unit catalytic enzyme, which degrades from 0.5 million proteins per minute in resting cells up to 2 million proteins per minute in dividing cells. Due to its control function in protein oscillation, regulation of cell cycle progression, signal transduction, transcription and apoptosis, the ubiquitin-proteasome system plays a considerable role in tumorigenesis and represents a very obvious target in cancer therapy. In addition, slightly structurally different inducible (by TNF or IFN for ex) proteasomes are involved in the processing of antigens (generating immunogenic peptides), hence they are called immunoproteaosmes.