Dual targeting of transformed and untransformed HTLV-1–infected T cells by DHMEQ, a potent and selective inhibitor of NF-κB, as a strategy for chemoprevention and therapy of adult T-cell leukemia

Abstract

AbstractHuman 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-κB (NF-κB) in the leukemic cells is essential for their growth and survival. Blocking NF-κB has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), and also examined its application to chemoprevention by selective purging of the HTLV-1-infected cells. DHMEQ inhibited NF-κB activation in primary ATL cells and cell lines derived from them and induced apoptotic cell death. NF-κB 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-κB is a potential molecular target for treatment and prevention of ATL. As a potent NF-κB inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine. (Blood. 2005;106:2462-2471)