The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo

Haematologica. 2012 Jul;97(7):1101-9. doi: 10.3324/haematol.2011.049981. Epub 2012 Jan 22.

Abstract

Background: Multiple myeloma is characterized by the accumulation of tumor plasma cells in the bone marrow. Despite therapeutic improvements brought by proteasome inhibitors such as bortezomib, myeloma remains an incurable disease. In a variety of human cancers, human immunodeficiency virus protease inhibitors (e.g. nelfinavir) effectively inhibit tumor progression, but their impact on myeloma is unknown. We assessed the in vitro and in vivo effects of nelfinavir on multiple myeloma.

Design and methods: The effects of nelfinavir (1-10 μM) on proteasome activity, proliferation and viability of myeloma cell lines and plasma cells from patients were assessed by measuring PERK, AKT, STAT3 and ERK1/2 phosphorylation and CHOP expression with immunoblotting or flow cytometry. The in vivo effect was assessed in NOD/SCID mice injected with luciferase expressing human myeloma cell lines and treated with nelfinavir at a dose of 75 mg/kg/day. Tumor progression was evaluated using a bioluminescent system.

Results: Nelfinavir inhibited 26S chymotrypsin-like proteasome activity, impaired proliferation and triggered apoptosis of the myeloma cell lines and fresh plasma cells. It activated the pro-apoptotic unfolded protein response pathway by inducing PERK phosphorylation and CHOP expression. Cell death triggered by nelfinavir treatment correlated with decreased phosphorylation of AKT, STAT3 and ERK1/2. Nelfinavir enhanced the anti-proliferative activity of bortezomib, dexamethasone and histone deacetylase inhibitors and delayed tumor growth in a myeloma mouse model.

Conclusions: These results suggest that nelfinavir, used at a pharmacological dosage, alone or in combination, may be useful in the treatment of myeloma. Our data provide a preclinical basis for clinical trials using nelfinavir in patients with myeloma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dexamethasone / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Genes, Reporter
  • HIV Protease Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Luciferases
  • Mice
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / enzymology
  • Multiple Myeloma / pathology*
  • Nelfinavir / pharmacology*
  • Plasma Cells / drug effects*
  • Plasma Cells / enzymology
  • Plasma Cells / pathology
  • Proteasome Endopeptidase Complex / drug effects*
  • Proteasome Endopeptidase Complex / metabolism
  • Pyrazines / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Boronic Acids
  • HIV Protease Inhibitors
  • Histone Deacetylase Inhibitors
  • Pyrazines
  • Bortezomib
  • Dexamethasone
  • Luciferases
  • Proteasome Endopeptidase Complex
  • Nelfinavir