Inhibition of NF-kappaB 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-kappaB activity has been detected in many tumors contributing to oncogenesis and tumor survival whereas inhibition of NF-kappaB activity has proved to enhance cell death induced by chemotherapeutic agents. Consequently, the use of BAY 11-7082, an irreversible inhibitor of IkappaB-alpha phosphorylation, could be beneficial in the treatment of certain tumors. Although there are several reports which demonstrate a transient activation of NF-kappaB by cytotoxic drugs, little is known about the role of NF-kappaB activation in the development of a chemoresistant phenotype in leukemic cells. In this study, we analyzed the relationship between NF-kappaB 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-kappaB-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-kappaB activity than the sensitive LBR- and the active complex contained both p50 and p65 subunits. BAY 11-7082 (3.5 microM) inhibited constitutive NF-kappaB 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-kappaB-inducible genes such as IL-10, IL-15, TNF-alpha and TGF-beta. Taken together, these data suggest that suppression of constitutive NF-kappaB activity by BAY 11-7082 may be a useful treatment for MDR leukemias.
Department of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires, IDEHU-CONICET, Argentina. marianag@ffyb.uba.ar
Mariana G
MG
García
Laura
L
Alaniz
Eloisi C
EC
Lopes
Guillermo
G
Blanco
Silvia E
SE
Hajos
Elida
E
Alvarez
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005786:Gene Expression Regulation / Q000187:drug effects; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016207:Cytokines; D052002:NF-kappa B p50 Subunit; D009570:Nitriles; D013450:Sulfones; D014750:Vincristine; D004317:Doxorubicin