bay-11-7082 and Leukemia--T-Cell

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.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cytokines; Doxorubicin; Drug Resistance, Multiple; Gene Expression Regulation; Leukemia, T-Cell; Mice; NF-kappa B p50 Subunit; Nitriles; Sulfones; Vincristine

We established a novel experimental model for human T-cell leukemia virus type 1 (HTLV-1)-induced tumor using NOD-SCID/gammac(null) (NOG) mice. This model is very useful for investigating the mechanism of tumorigenesis and malignant cell growth of adult T-cell leukemia (ATL)/lymphoma, which still remains unclear. Nine HTLV-1-infected cell lines were inoculated subcutaneously in the postauricular region of NOG mice. As early as 2 to 3 weeks after inoculation, seven cell lines produced a visible tumor while two transformed cell lines failed to do so. Five of seven lines produced a progressively growing large tumor with leukemic infiltration of the cells in various organs that eventually killed the animals. Leukemic cell lines formed soft tumors, whereas some transformed cell lines developed into hemorrhagic hard tumors in NOG mice. One of the leukemic cell lines, ED-40515(-), was unable to produce visible tumors in NOD-SCID mice with a common gamma-chain after 2 weeks. In vivo NF-kappaB DNA binding activity of the ED-40515(-) cell line was higher and the NF-kappaB components were changed compared to cells in vitro. Bay 11-7082, a specific and effective NF-kappaB inhibitor, prevented tumor growth at the sites of the primary region and leukemic infiltration in various organs of NOG mice. This in vivo model of ATL could provide a novel system for use in clarifying the mechanism of growth of HTLV-1-infected cells as well as for the development of new drugs against ATL.

Topics: Animals; Antineoplastic Agents; Cell Line, Transformed; Disease Models, Animal; Graft Survival; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Leukemia, T-Cell; Lymphoma; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Neoplasms, Experimental; NF-kappa B; Nitriles; Organic Chemicals; Sulfones