University of the Ryukyus · Center for Research Infrastructure Management · 助教

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• Evaluation of artesunate for the treatment of adult T-cell leukemia/lymphoma.2020 · Adult T-cell leukemia/lymphoma (ATLL) is an aggressive disease caused by infection with human T-cell leukemia virus type 1 (HTLV-1). Successful treatment is limited by resistance to chemotherapies. Therefore, there is an urgent need to develop novel effective strategies. Artesunate (ART), a widely used antimalarial compound, has been shown to exert cytotoxicity. Here, we aimed to assess the anti-ATLL activities of ART and to elucidate the possible molecular mechanisms involved in this effect. Compared with uninfected T cells, HTLV-1-infected T-cell lines were sensitive to ART-induced cytotoxicity. ART caused cell cycle arrest at G1 and/or G2/M phases, which was associated with decreased expression of cyclin dependent kinase 1/2/4/6, cyclin B1/D2/E and c-Myc, and increased expression of p21. ART-induced apoptosis corresponded to activation of caspase-8/9/3; decreased expression of Bcl-xL, Bcl-2, myeloid cell leukemia-1, survivin, X-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis 1/2; and increased expression of Bak. ART increased intracellular reactive oxygen species and activation of the DNA damage marker γ-H2AX. Moreover, ART-induced cytotoxicity was partly reversed by treatment with a reactive oxygen species scavenger, iron chelator, and necroptosis or ferroptosis inhibitor, suggesting the involvement of caspase-dependent and -independent lethal pathways. These effects were correlated with inhibition of nuclear factor-κB and activator protein-1 signaling through dephosphorylation of IκBα, IκB kinase (IKK) α and IKKβ, and decreased expression of JunB and JunD. Importantly, intraperitoneal injection with ART lowered tumor burden in an ATLL murine model. These preclinical results provide a rationale for evaluating the efficacy of ART in patients with ATLL.
• The role of CUDC-907, a dual phosphoinositide-3 kinase and histone deacetylase inhibitor, in inhibiting proliferation of adult T-cell leukemia.2020 · Ishikawa C, Mori N
• MALT-1 as a novel therapeutic target for adult T-cell leukemia.2020 · Ishikawa C, Mori N
• The anti-malaria agent artesunate exhibits cytotoxic effects in primary effusion lymphoma.2020 · Ishikawa C, Mori N

• 核内輸送蛋白質インポーチンに着眼した成人T細胞白血病の発症機構の解明と治療戦略2017 · 基盤研究(C)
• LIMホメオドメイン転写因子ISL-1のATL発症・進展への関与2015 · 若手研究(B)
• インターフェロン調節因子IRF5による成人T細胞白血病・リンパ腫細胞の運命制御2013 · 若手研究(B)
• EBウイルス関連T/NK細胞増多症の細胞生存シグナルの解明と治療法の開発

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