dehydroxymethylepoxyquinomicin and Leukemia-Lymphoma--Adult-T-Cell

Adult T-cell leukemia/lymphoma (ATL), a fatal T-cell leukemia/lymphoma resistant to chemotherapy, is caused by human T-cell leukemia/lymphoma virus type I (HTLV-1), occurring even after 50 years of clinical latency from initial transmission. Constitutively activated nuclear factor kappaB (NF-kappaB) appears to be a molecular basis for the aberrant growth and cytokine gene expression observed in ATL cells, thereby serving as an ideal target in the treatment of ATL. Dehydroxymethylepoxyquinomicin (DHMEQ) is a new NF-kappaB inhibitor that is a 5-dehydroxymethyl derivative of epoxyquinomicin C, having a 4-hydroxy-5,6-epoxycyclohexenone structure similar to panepoxydone. This unique compound acts in the translocation of NF-kappaB into the nucleus. Dehydroxymethylepoxyquinomicin inhibits NF-kappaB activation in ATL cells and induces apoptotic cell death. In addition, DHMEQ selectively targets HTLV-1-infected cells in the peripheral blood of virus carriers in vitro, resulting in a decreased number of infected cells. We have concluded that blocking NF-kappaB is a potential strategy for the treatment and prevention of ATL. As a potent NF-kappaB inhibitor, DHMEQ is a promising compound for translating this strategy into clinical medicine.

Topics: Adult; Animals; Antineoplastic Agents; Apoptosis; Benzamides; Cyclohexanones; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphoma, T-Cell; NF-kappa B

Topics: Benzamides; Boronic Acids; Bortezomib; Carrier State; Cyclohexanones; HIV Protease Inhibitors; Human T-lymphotropic virus 1; Humans; Infectious Disease Transmission, Vertical; Leukemia-Lymphoma, Adult T-Cell; NF-kappa B; Protease Inhibitors; Pyrazines; Ritonavir; Stem Cell Transplantation; Transplantation, Homologous

We previously discovered (-)-DHMEQ as a selective inhibitor of NF-κB, and it was shown to suppress many cancer and inflammation models in animals. (-)-DHMEQ directly binds to NF-κB components to inhibit DNA binding, and moreover, it often inhibits nuclear translocation of NF-κB. The mechanism of inhibiting nuclear translocation has been elucidated for RelB, a main noncanonical NF-κB component. However, it was not elucidated for p65, a main canonical NF-κB component. In the present research, we studied how (-)-DHMEQ inhibits nuclear localization of p65. First, (-)-DHMEQ inhibited p65 nuclear accumulation in adult T-cell leukemia MT-2 cells in which canonical p65 is constitutively activated. But there was no change in the stability and importin-α3 affinity of p65. Then, we prepared a p65 mutant protein with Arg35Ala and Tyr36Ala (AA) mutations having no DNA-binding ability in HeLa cells. The p65 AA mutant showed reduced nuclear localization without changing the stability and importin affinity. Taken together, the mechanism of inhibition is different between RelB and p65, and inhibition of p65 nuclear localization is likely to be due to the inhibition of DNA binding changing the equilibrium between the nuclear and cytoplasmic amounts of p65.

Topics: Benzamides; Breast Neoplasms; Cell Line, Tumor; Cell Nucleus; Cyclohexanones; DNA; Enzyme Activation; Gene Expression; HeLa Cells; Humans; Leukemia-Lymphoma, Adult T-Cell; Models, Biological; Mutation; NF-kappa B; Protein Binding; Protein Transport; Transcription Factor RelA

Adult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type I (HTLV-I). The NF-kappaB pathway is activated in ATL cells and in virus-infected cells, and plays a central role in oncogenesis. We examined the effect of the novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on a well-characterized HTLV-I-infected cell line, HUT-102, in vitro and in vivo. DHMEQ inhibited translocation of NF-kappaB p65 to the nucleus and induced apoptotic cell death in vitro. In vivo, DHMEQ inhibited the growth and infiltration of HUT-102 tumor cells transplanted subcutaneously in SCID mice lacking natural killer cell activity.

Topics: Active Transport, Cell Nucleus; Animals; Benzamides; Cell Line; Cell Nucleus; Cyclohexanones; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Mice; Mice, SCID; Neoplasm Proteins; Neoplasm Transplantation; Transcription Factor RelA

Adult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type I (HTLV-I). The nuclear transcription factor, NF-kappaB, is induced by HTLV-I and is central to the ensuing neoplasia. To examine the effect of a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on ATL in vivo, we developed an improved severe combined immunodeficiency (SCID) mouse model for ATL. Five-week-old SCID mice in which natural killer (NK) cell activity had been eliminated were inoculated intraperitoneally with the HTLV-I-infected cell lines, TL-Om1, MT-1, MT-2 and HUT-102. No engraftment of TL-Om1 cells and little tumorigenesis of MT-1 cells were detected 40 days after injection. In contrast, inoculation of mice with MT-2 and HUT-102 cells elicited high mortality, 100% frequency of gross tumor formation and tumor cell infiltration of various organs, all of which were reduced by coadministration of DHMEQ during the inoculation. Moreover, tumors from mice treated with DHMEQ had a high frequency of apoptosis. These results suggest that DHMEQ induces apoptosis in HTLV-I-transformed cells in vivo, resulting in inhibition of tumor formation and organ infiltration, thereby enhancing survival.

Topics: Animals; Antineoplastic Agents; Apoptosis; Base Sequence; Benzamides; Binding Sites; Cell Division; Cell Line, Tumor; Consensus Sequence; Cyclohexanones; Disease Models, Animal; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Mice; NF-kappa B; Transplantation, Heterologous

Human T-cell leukemia virus type I (HTLV-1) causes adult T-cell leukemia (ATL), a fatal T-cell leukemia resistant to chemotherapy, after more than 50 years of clinical latency from transmission through breast-feeding. Polyclonal expansion of virus-infected T cells predisposes them to transformation. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in the leukemic cells is essential for their growth and survival. Blocking NF-kappaB has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), and also examined its application to chemoprevention by selective purging of the HTLV-1-infected cells. DHMEQ inhibited NF-kappaB activation in primary ATL cells and cell lines derived from them and induced apoptotic cell death. NF-kappaB inhibition down-regulated expression of genes involved in antiapoptosis or cell-cycle progression. DHMEQ protected severe combined immunodeficiency (SCID) mice inoculated with HTLV-1-transformed cells from death. In addition, DHMEQ selectively targeted HTLV-1-infected cells in the peripheral blood of virus carriers in vitro, resulting in a decreased number of infected cells. We conclude that NF-kappaB is a potential molecular target for treatment and prevention of ATL. As a potent NF-kappaB inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Caspases; Cell Cycle; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Cell Proliferation; Cyclohexanones; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation, Neoplastic; Genes, Reporter; Human T-lymphotropic virus 1; Humans; Immunoblotting; Immunohistochemistry; Jurkat Cells; K562 Cells; Leukemia-Lymphoma, Adult T-Cell; Leukemia, T-Cell; Leukocytes, Mononuclear; Male; Mice; Mice, SCID; Microscopy, Fluorescence; Molecular Weight; NF-kappa B; Proviruses; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; Time Factors; Tumor Suppressor Protein p53