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

GARCÍA MARIANA; ALANIZ LAURA; LOPES ELOISI C; BLANCO GUILLERMO; HAJOS SILVIA E; ALVAREZ ELIDA

LEUKEMIA RESEARCH

Elseiver Science Ltd

Lugar: Exert EX1 2AH, U.K; Año: 2005 vol. 29 p. 1425 - 1434

0145-2126

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