成人 T 细胞白血病/淋巴瘤 (ATL) 是由人类 T 细胞嗜淋巴细胞病毒 I 型 (HTLV-1) 引起的侵袭性 T 细胞白血病/淋巴瘤。 Acadesine 或 5-氨基咪唑-4-甲酰胺核苷 (AICAR) 是一种 AMP 激活蛋白激酶 (AMPK) 激活剂，最近显示对 B 细胞慢性淋巴细胞白血病具有肿瘤抑制作用，但对 ATL 没有肿瘤抑制作用。本研究评估了 AICAR 对 ATL 相关细胞系的细胞毒作用及其抗肿瘤活性。在这里，我们证明 AICAR 通过 ATL 相关细胞系（S1T、MT-1 和 MT-2）的细胞凋亡和线粒体膜去极化诱导细胞死亡，但对未感染 HTLV-1 的 Jurkat 细胞则不然。然而，AICAR 并没有增加 AMPKα 的磷酸化水平。此外，AICAR 还增加了死亡受体 (DR) DR4 和 DR5 以及坏死性凋亡相关蛋白（包括磷酸化受体相互作用蛋白家族成员和混合谱系激酶结构域样蛋白）的表达。有趣的是，HTLV-1 Tax（一种 HTLV-1 编码的致癌因子）并不影响 AICAR 诱导的细胞凋亡。此外，AICAR 还能抑制 NOD/SCID/gamma 小鼠体内人 ATL 肿瘤异种移植物的生长。总之，这些结果表明 AICAR 在 ATL 相关细胞系中诱导 AMPK 独立的细胞死亡，并具有抗肿瘤活性，表明它可能是 ATL 的治疗剂。版权所有 © 2023。由 Elsevier B.V 出版。

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell leukemia/lymphoma caused by human T-cell lymphotropic virus type I (HTLV-1). Acadesine or 5-aminoimidazole-4-carboxamide riboside (AICAR) is an AMP-activated protein kinase (AMPK) activator that was recently shown to have tumor suppressive effects on B cell chronic lymphocytic leukemia, but not ATL. This study evaluated the cytotoxic effects of AICAR on ATL-related cell lines and its anti-tumor activity. Here, we demonstrated that AICAR induced cell death via apoptosis and the mitochondrial membrane depolarization of ATL-related cell lines (S1T, MT-1, and MT-2) but not non-HTLV-1-infected Jurkat cells. However, AICAR did not increase the phosphorylation levels of AMPKα. In addition, AICAR increased the expression of the death receptors (DR) DR4 and DR5, and necroptosis-related proteins including phosphorylated receptor-interacting protein family members and the mixed lineage kinase domain-like protein. Interestingly, HTLV-1 Tax, an HTLV-1-encoded oncogenic factor, did not affect AICAR-induced apoptosis. Furthermore, AICAR inhibited the growth of human ATL tumor xenografts in NOD/SCID/gamma mice in vivo. Together, these results suggest that AICAR induces AMPK-independent cell death in ATL-related cell lines and has anti-tumor activity, indicating that it might be a therapeutic agent for ATL.Copyright © 2023. Published by Elsevier B.V.