Ritonavir, nelfinavir, saquinavir and lopinavir induce proteotoxic stress in acute myeloid leukemia cells and sensitize them for proteasome inhibitor treatment at low micromolar drug concentrations.

Abstract

BACKGROUND:

Protein metabolism is an innovative potential therapeutic target for AML. Proteotoxic stress (PS) sensitizes malignant cells for proteasome inhibitor treatment. Some HIV protease inhibitors (HIV-PI) induce PS and may therefore be combined with proteasome inhibitors to achieve PS-targeted therapy of AML.

METHODS:

We investigated the effects of all nine approved HIV-PI alone and in combination with proteasome inhibitors on AML cell lines and primary cells in vitro.

RESULTS:

Ritonavir induced cytotoxicity and PS at clinically achievable concentrations, and induced synergistic PS-triggered apoptosis with bortezomib. Saquinavir, nelfinavir and lopinavir were likewise cytotoxic against primary AML cells, triggered PS-induced apoptosis, inhibited AKT-phosphorylation and showed synergistic cytotoxicity with bortezomib and carfilzomib at low micromolar concentrations. Exclusively nelfinavir inhibited intracellular proteasome activity, including the β2 proteasome activity that is not targeted by bortezomib/carfilzomib.

CONCLUSIONS:

Of the nine currently approved HIV-PI, ritonavir, saquinavir, nelfinavir and lopinavir can sensitize AML primary cells for proteasome inhibitor treatment at low micromolar concentrations and may therefore be tested clinically toward a proteotoxic stress targeted therapy of AML.

• Authors: Marianne Kraus, Hendrik Müller-Ide, Thomas Rückrich, Jürgen Bader, Herman Overkleeft, Christoph Driessen
• Journal: Leukemia research (Leuk Res) Vol. 38 Issue 3 Pg. 383-92 (Mar 2014) ISSN: 1873-5835 [Electronic] England
• PMID: 24418752 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Ltd.

Chemical References

• Cytotoxins
• HIV Protease Inhibitors
• Proteasome Inhibitors
• Lopinavir
• Proto-Oncogene Proteins c-akt
• Proteasome Endopeptidase Complex
• Nelfinavir
• Saquinavir
• Ritonavir

Topics

• Apoptosis (drug effects)
• Cytotoxins (pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Gene Expression Regulation, Leukemic
• HIV Protease Inhibitors (pharmacology)
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Lopinavir (pharmacology)
• Nelfinavir (pharmacology)
• Phosphorylation
• Proteasome Endopeptidase Complex (drug effects, genetics)
• Proteasome Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Ritonavir (pharmacology)
• Saquinavir (pharmacology)
• Signal Transduction
• Tumor Cells, Cultured