文章：

口服HSP90抑制剂17-DMAG可干预肿瘤细胞向多器官的浸润，延长ATL模型小鼠的生存期

Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice

原文发布日期：2013-08-16

DOI: 10.1038/bcj.2013.30

类型: Original Article

开放获取: 是

英文摘要：

In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90’s ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression.

摘要翻译： 

在人类T淋巴细胞病毒1型（HTLV-1）携带者或成人T细胞白血病（ATL）患者的外周血白细胞中，核因子κB（NF-κB）介导的抗凋亡信号通路被HTLV-1编码的癌蛋白Tax持续激活。Tax通过与IκB激酶调节亚基NEMO（NF-κB必需调节因子）相互作用来激活NF-κB，该相互作用部分由分子伴侣热休克蛋白90（HSP90）及其辅助伴侣细胞分裂周期蛋白37（CDC37）维持。抗生素格尔德霉素（GA）通过抑制HSP90的ATP结合来阻断其与客户蛋白的正常相互作用。对表达Tax的ATL转化细胞系（C8166和MT4）施用新型水溶性低毒性GA衍生物——17-二甲氨基乙氨基-17-去甲氧基格尔德霉素盐酸盐（17-DMAG），可诱导Tax显著降解。17-DMAG还能促使C8166、MT4及其他ATL细胞系发生生长停滞和细胞凋亡，但对正常外周血白细胞无明显影响。在Tax转染的HEK293细胞中，17-DMAG还下调了Tax介导的细胞内信号，包括NF-κB、激活蛋白1或HTLV-1长末端重复序列的激活。对移植淋巴瘤性转基因Lck-Tax细胞或产生HTLV-1的肿瘤细胞的ATL模型小鼠口服17-DMAG，能显著减弱多器官侵袭性浸润，抑制病毒新生复制并延长生存期。这些研究结果确认17-DMAG是阻止ATL进展的潜在候选药物。

原文链接：

Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice