Mechanisms of proteasome inhibitor action and resistance in cancer

Drug Resist Updat. Aug-Oct 2008;11(4-5):164-79. doi: 10.1016/j.drup.2008.08.002. Epub 2008 Sep 24.

Abstract

Proteasome inhibitors (PIs), such as bortezomib, carfilzomib or NPI-0052, have excellent clinical activity in patients with multiple myeloma and mantle cell lymphoma, and they are currently being evaluated in combination with other agents in patients with solid tumors. Although they exert broad effects on cancer cells, their ability to (1) stabilize pro-apoptotic members of the BCL-2 family, (2) inhibit the two major pathways leading to NFkappaB activation, and (3) cause the build-up of misfolded proteins appear to be particularly important. In addition, PIs may disrupt tumor-stromal interactions that drive NFkappaB activation and angiogenesis and in such a way sensitize cancer cells to other agents. Still, drug resistance ultimately emerges in all tumors that initially respond to PIs. This review provides an overview of the current thinking about how PIs may kill cancer cells exemplified for pancreatic cancer and the possible mechanisms involved in resistance to PIs.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Cysteine Proteinase Inhibitors / therapeutic use*
  • Drug Resistance, Neoplasm*
  • Humans
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors*
  • Protein Folding / drug effects
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Cysteine Proteinase Inhibitors
  • NF-kappa B
  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex