Inhibition of NF-κB activity by BAY 11-7082 increases apoptosis in multidrug resistant leukemic T-cell lines

Multidrug resistance (MDR) is the main reason for failure of cancer therapy with resistance to apoptosis being one of the mechanisms involved. Constitutive NF-kappa B activity has been detected in many tumors contributing to oncogenesis and tumor survival whereas inhibition of NF-kappa B activity has proved to enhance cell death induced by chemotherapeutic agents. Consequently, the use of BAY 11-7082, an irreversible inhibitor of I kappa B-alpha phosphorylation, could be beneficial in the treatment of certain tumors. Although there are several reports which demonstrate a transient activation of NF-kappa B by cytotoxic drugs, little is known about the role of NF-kappa B activation in the development of a chemoresistant phenotype in leukemic cells. In this Study, we analyzed the relationship between NF-kappa B and the survival of murine leukemic drug resistant cell lines. The modulation of this transcription factor by BAY 11-7082 and the chemotherapeutic agents vincristine and doxorubicin was evaluated. The effect of BAY 11-7082 on the expression of genes containing NF-kappa B-binding sites was also studied. We found that the cell lines LBR-V160 and LBR-D160 (resistant to vincristine and doxorubicin, respectively) presented higher constitutive NF-kappa B activity than the sensitive LBR- and the active complex contained both p50 and p65 subunits. BAY 11-7082 (3.5 mu M) inhibited constitutive NF-kappa B activity in the three cell lines whereas the anticancer agents did not. Treatment with BAY 11-7082 induced a higher percentage of apoptosis in LBR-V160 and LBR-D160 than in LBR-. Cells treated with BAY 11-7082 displayed modulation of NF-kappa B-inducible genes such as IL-10 IL-15 TNF-alpha and TGF-beta. Taken together. these data suggest that suppression of constitutive NF-kappa B activity by BAY 11-7082 may be a useful treatment for MDR leukemias. (C) 2005 Elsevier Ltd. All rights reserved.