Blocking NF-kappaB as a potential strategy to treat adult T-cell leukemia/lymphoma

Abstract

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.