Advances in the understanding of mechanisms and therapeutic use of bortezomib

Discov Med. 2011 Dec;12(67):471-80.


The ubiquitin-proteasome pathway regulates many basic cellular processes and has been proven to be a promising target for cancer therapy. Bortezomib is the first U.S. Food and Drug Administration (FDA) approved proteasome inhibitor used in the treatment of newly diagnosed multiple myeloma, relapsed/refractory multiple myeloma, and mantle cell lymphoma. The anti-cancer mechanisms of bortezomib elucidated by preclinical studies include: upregulation of proapoptotic proteins (e.g., Noxa, IκB), inhibition of NFκB and its anti-apoptotic target genes, suppression of several anti-apoptotic proteins (e.g., Bcl-XL, Bcl-2, and STAT-3), down-regulation of expression of several proteins involved in DNA repair pathways, and induction of endoplasmic reticulum (ER) stress and pro-apoptotic Unfolded Protein Response (UPR). Bortezomib has potent chemo-/radio-sensitizing effects and can overcome traditional drug resistance in tumors when used in combination with potential chemotherapies. Although bortezomib has been successful in improving clinical outcomes when used in hematological malignancies, relapse may occur in those patients who responded initially. Furthermore, some cytotoxicities (such as peripheral neuropathy) were found to be associated with bortezomib treatment. These observations have encouraged researchers to search for the next generation proteasome inhibitors (including carfilzomib and marizomib) that could overcome bortezomib resistance and have improved properties, reduced toxicities, and broader anticancer activities, based on the lessons learned from the mechanisms and use of bortezomib. This review summarizes the current status of bortezomib as well as several other proteasome inhibitors that are currently under clinical and preclinical investigation.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Boronic Acids / adverse effects
  • Boronic Acids / chemistry
  • Boronic Acids / pharmacology
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Clinical Trials as Topic
  • Drug Resistance / drug effects
  • Humans
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Pyrazines / adverse effects
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use*
  • Signal Transduction / drug effects
  • Ubiquitin / metabolism


  • Boronic Acids
  • Proteasome Inhibitors
  • Pyrazines
  • Ubiquitin
  • Bortezomib
  • Proteasome Endopeptidase Complex