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

2005; Elsevier BV; Volume: 29; Issue: 12 Linguagem: Inglês

10.1016/j.leukres.2005.05.004

1873-5835

Mariana Garcı́a, Laura Alaniz, Eloisi Caldas Lopes, Guillermo Blanco, Silvia E. Hajos, Élida Álvarez,

Natural Compounds in Disease Treatment

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