Proteasome Pathway

The ubiquitin proteasome pathway (UPP) plays a central role in cellular homeostasis in the processing and degradation of proteins, including those that regulate cell-cycle progression, apoptosis, and DNA repair.1 The 26S proteasome, a key element of the UPP, is formed by the 20S proteolytic core and 19S regulatory particle.2,3 Polyubiquitinated proteins that are destined for degradation by the UPP are recognized by the 19S particle and directed to the 20S core, where proteolytic cleavage is mediated by 3 β subunits: β1 (caspase-like activity), β2 (trypsin-like activity), and β5 (chymotrypsin-like activity).4-6

Inhibition of proteasome activity may result in growth arrest and cell death due to the rapid accumulation of regulatory proteins and the induction of apoptotic signaling within the cell.7,8 In vitro studies have found high levels of proteasome activity in tumor cells compared with normal cells, making the proteasome a rational therapeutic target in oncology, particularly for the treatment of multiple myeloma (MM) due to the high levels of immunoglobulins produced by myeloma cells.9,10 Enhanced osteoblasts (bone-forming cells) and reduced osteoclasts (bone-destroying cells) have been shown with proteasome inhibition in preclinical studies of MM.11,12 Proteasome inhibition has been explored as a therapeutic strategy in MM.13 Next-generation proteasome inhibitors that may overcome inherent and acquired bortezomib resistance and that may exhibit broad anti-cancer activity are currently under clinical development.14

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

References

  1. Kybuczkova L, et al. J Cell Mol Med. 2014;18:947-961.
  2. Heinemeyer W, et al. J Biol Chem. 1997;272:25200-25209.
  3. Jager S, et al. J Mol Biol. 1999;291:997-1013.
  4. Adams J. Cancer Treat Rev. 2003;29(suppl 1):3-9.
  5. Ciechanover A. Cell. 1994;79:13-21.
  6. Ciechanover A. EMBO J. 1998;17:7151-7160.
  7. Groll M, et al. Nature. 1997;386:463-471.
  8. Obeng EA, et al. Blood. 2006;107:4907-4916.
  9. Genci S, et al. EMBO J. 2006;25:1104-1113.
  10. Brewer JW, et al. Proc Natl Acad Sci U S A. 1999;96:8505-8510.
  11. Pennisi A, et al. Am J Hematol. 2009;84:6-14.
  12. Hurchla MA, et al. Leukemia. 2013;27:430-440.
  13. NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. V2.2015.
  14. Potts BC, et al. Curr Cancer Drug Targets. 2011;11:254-284.