期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 872, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2020.172953
关键词
Adult T-cell leukemia/lymphoma; Human T-cell leukemia virus type 1; Artesunate; Reactive oxygen species; Nuclear factor-kappa B; Activator protein-1
资金
- JSPS KAKENHI [17K07175]
- Grants-in-Aid for Scientific Research [17K07175] Funding Source: KAKEN
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 Tcell lines were sensitive to ART-induced cytotoxicity. ART caused cell cycle arrest at G(1) and/or G(2)/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 gamma-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-kappa B and activator protein-1 signaling through dephosphorylation of I kappa B alpha, I kappa B kinase (IKK) alpha and IKK beta, 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.
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