ABSTRACT
Adult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type I (HTLV-I), which induces nuclear factor-kappaB (NF-kappaB), a molecule central to the ensuing neoplasia. The NF-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) has been shown to inhibit NF-kappaB activation in Tax-expressing HTLV-I-infected cells. In this study, we used NOD/SCID beta2-microglobulin(null) mice to show that intraperitoneal inoculation with Tax-deficient ATL cell lines caused rapid death, whereas DHMEQ-treated mice survived. Furthermore, DHMEQ treatment after subcutaneous inoculation inhibited the growth of transplanted ATL cells. These results demonstrate that DHMEQ has therapeutic efficacy on ATL cells, regardless of Tax expression.
Subject(s)
Benzamides/pharmacology , Cyclohexanones/pharmacology , Gene Products, tax/deficiency , Leukemia, T-Cell/prevention & control , Xenograft Model Antitumor Assays/methods , Adult , Animals , Apoptosis/drug effects , Benzamides/therapeutic use , Cell Line, Tumor , Cyclohexanones/therapeutic use , Gene Products, tax/genetics , Human T-lymphotropic virus 1/genetics , Human T-lymphotropic virus 1/metabolism , Humans , Leukemia, T-Cell/pathology , Leukemia, T-Cell/virology , Mice , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Analysis , Tumor Burden , beta 2-Microglobulin/genetics , beta 2-Microglobulin/metabolismABSTRACT
Adult T-cell leukemia (ATL) was first described in 1977. A link between ATL and human T-cell leukemia virus type 1 (HTLV-1) was clearly established in the early 1980s. Over the years, many aspects of HTLV-1-induced cellular dysfunctions have been clarified. However, the detailed mechanism behind ATL occurrence remains unsolved. Presently, we are still unable to explain the absence of viral Tax protein (thought to play a central role in T-cell transformation) in more than 50% of ATL cells. A novel HTLV-1 HBZ protein, encoded on the negative strand, was characterized by our group and is currently the subject of intensive research efforts to determine its function in viral replication and/or pathophysiology. Recently, 4 studies reported on the existence of different HBZ isoforms and have investigated on their function in both ATL cells or animal models. One report suggests that the HBZ gene might have a bimodal function (at the mRNA and protein levels), which could represent an uncharacterized strategy to regulate viral replication and proliferation of infected T cells.
