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

GARCÍA MG; ALANIZ L; LOPES EC; BLANCO G; HAJOS SE; ALVAREZ E

LEUKEMIA RESEARCH

Año: 2005 vol. 29 p. 1425 - 1434

0145-2126

Multidrug resistance (MDR) is the main reason for failure of cancer therapy with resistance to apoptosis being one of the mechanisms involved. Constitutive NF-kB activity has been detected in many tumors contributing to oncogenesis and tumor survival whereas inhibition of NF-kB activity has proved to enhance cell death induced by chemotherapeutic agents. Consequently, the use of BAY 11-7082, an irreversible inhibitor of IkB-a phosphorylation, could be beneficial in the treatment of certain tumors. Although there are several reports which demonstrate a transient activation of NF-kB by cytotoxic drugs, little is known about the role of NF-kB activation in the development of a chemoresistant phenotype in leukemic cells. In this study, we analyzed the relationship between NF-kB 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-kB-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-kB activity than the sensitive LBR- and the active complex contained both p50 and p65 subunits. BAY 11-7082 (3.5 mM) inhibited constitutive NF-kB 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-kB-inducible genes such as IL-10, IL-15, TNF-a and TGF-b. Taken together, these data suggest that suppression of constitutive NF-kB activity by BAY 11-7082 may be a useful treatment for MDR leukemias.