Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice.
Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice.
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DOI：
10.1038/bcj.2013.30
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发表时间：
2013-08-16
影响因子：
12.8
通讯作者：
Iha, H.
中科院分区：
文献类型：
--
作者：
Ikebe, E.;Kawaguchi, A.;Tezuka, K.;Taguchi, S.;Hirose, S.;Matsumoto, T.;Mitsui, T.;Senba, K.;Nishizono, A.;Hori, M.;Hasegawa, H.;Yamada, Y.;Ueno, T.;Tanaka, Y.;Sawa, H.;Hall, W.;Minami, Y.;Jeang, K. T.;Ogata, M.;Morishita, K.;Hasegawa, H.;Fujisawa, J.;Iha, H.
在人类嗜t淋巴病毒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（PBLs）中，核因子κ b （NF-κB）介导的抗凋亡信号主要由HTLV-1编码的癌蛋白Tax组成性激活。Tax与I κB激酶调控亚基NEMO （NF-κB必需调节剂）相互作用，激活NF-κB，这种相互作用部分由分子伴侣热休克蛋白90 （HSP90）及其共同伴侣细胞分裂周期37 （CDC37）维持。抗生素格尔达霉素（GA）抑制HSP90的ATP结合，使其与客户蛋白适当相互作用。将一种新型的水溶性、毒性较低的GA衍生物17-二甲氨基乙胺-17-去甲氧基格尔达霉素盐酸盐（17-DMAG）应用于表达Tax的ATL转化细胞系C8166和MT4，可诱导Tax的显著降解，17-DMAG还可促进C8166和MT4等ATL细胞系的生长停滞和细胞凋亡，尽管这种处理对正常的PBLs没有明显影响。17-DMAG还下调了税介导的细胞内信号，包括NF-κB、激活蛋白1或HTLV-1长末端重复序列的激活。口服17-DMAG给移植了淋巴瘤转基因Lck-Tax （Lck近端启动子驱动的Tax转基因）细胞或产生htlv -1的肿瘤细胞的ATL模型小鼠，可显著减少对多器官的侵袭性浸润，抑制新生病毒的产生，延长生存期。这些观察结果确定17-DMAG是预防ATL进展的有希望的候选药物。
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.
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