Antiproliferative and proapoptotic effects of proteasome inhibitors and their combination with histone deacetylase inhibitors on leukemia cells.

Abstract

New chemotherapeutic agents are still required to further optimise treatment of leukemia patients. Proteasome inhibition by bortezomib, PR-171 (carfilzomib) and NPI-0052 (salinosporamide A) has been successfully used for the treatment of multiple myeloma and mantle cell lymphoma and is considered also as novel treatment strategy in leukemia. Combination of proteasome inhibitors bortezomib and NPI-0052 induces synergistic anti-multiple myeloma activity both in vitro using multiple myeloma cells and in vivo in a human plasmacytoma xenograft mouse model. Cell death resulting from proteasome inhibition requires caspase activation and increased levels of reactive oxygen species. While bortezomib induces several caspases, NPI-0052 activates predominantly caspase-8-dependent pathway. We studied the effect of bortezomib (10 nM) on DNA synthesis and apoptosis in human acute myeloid cell lines KASUMI-1, ML-1, ML-2 and CTV-1 cells. Bortezomib was potent inhibitor of DNA synthesis in all four types of leukemia cells and induced apoptosis in KASUMI-1, ML-2 and CTV-1 cells but not in ML-1 cells. Other research groups showed that histone deacetylase inhibitors (valproic acid or benzamide derivative MS-275) in combination with NPI-0052 or PR-171 induced greater levels of acute leukemia cell death than in combination with bortezomib. Proteasome inhibition as monotherapy and its combination with many conventional therapies as novel treatment strategies in leukemia are promising. Malignant cells are more sensitive to this treatment than normal hematopoietic cells.

• Authors: Ota Fuchs, Dana Provaznikova, Iuri Marinov, Katerina Kuzelova, Ivan Spicka
• Journal: Cardiovascular & hematological disorders drug targets (Cardiovasc Hematol Disord Drug Targets) Vol. 9 Issue 1 Pg. 62-77 (Mar 2009) ISSN: 2212-4063 [Electronic] United Arab Emirates
• PMID: 19275578 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Boronic Acids
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Lactones
• Oligopeptides
• Protease Inhibitors
• Pyrazines
• Pyrroles
• Bortezomib
• marizomib
• carfilzomib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Boronic Acids (pharmacology)
• Bortezomib
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Histone Deacetylase Inhibitors
• Humans
• Lactones (pharmacology)
• Leukemia (drug therapy, physiopathology)
• Oligopeptides (pharmacology)
• Protease Inhibitors (pharmacology)
• Pyrazines (pharmacology)
• Pyrroles (pharmacology)