Proteasome Inhibition in Myelodysplastic Syndromes and Acute Myelogenous Leukemia Cell Lines

Abstract

In this work, effects of bortezomib on apoptosis, clonal progenitor growth, cytokine production, and NF-κB expression in patients with MDS with cytopenias requiring transfusion support are examined. Bortezomib increased apoptosis in marrow mononuclear cells but had no effects on CFU-GM, BFU-E, or CFU-L content. No consistent effects on NF-κB activation in vivo were noted. To further define the role of bortezomib in AML and MDS, we examined it in combination with several targeted agents and chemotherapeutic agents in vitro. Combinations with arsenic trioxide, sorafenib, and cytarabine demonstrated synergistic in vitro effects in AML cell lines.

Keywords: :

• Leukemias
• Signal transduction
• Treatment

ACKNOWLEDGMENTS

This work was supported by NIH grant R21CA112835 (JLL). Bortezomib for the clinical trial was provided by Millennium. We thank Nicole Proia for clinical trial and regulatory coordination, and Elva Mikk for aid in manuscript preparation. The clinical trial described here is registered at http://.clincaltrials.gov (#NCT00262873).