Blocking NF-kappaB as a potential strategy to treat adult T-cell leukemia/lymphoma.
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.
Horie
Ryouichi
R
Department of Hematology, School of Medicine, Kitasato University, Kanagawa, Japan. rhorie@med.kitasato-u.ac.jp
Watanabe
Toshiki
T
Umezawa
Kazuo
K
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D003512:Cyclohexanones / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin