Efficiency of AUY922 in mice with adult T-cell leukemia/lymphoma.
Efficiency of AUY922 in mice with adult T-cell leukemia/lymphoma.
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DOI：
10.3892/ol.2016.4624
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发表时间：
2016-07
期刊：
影响因子：
2.9
通讯作者：
Mori N
中科院分区：
文献类型：
--
作者：
Ishikawa C;Senba M;Mori N
成人T细胞白血病/淋巴瘤（ATLL）是由人T细胞白血病病毒1型（HTLV-1）引起的侵袭性恶性肿瘤。ATLL与不良预后相关，主要是由于对化疗的耐药性，这突出了对替代疗法的需求。分子伴侣热休克蛋白（HSP）90是参与ATLL发病和进展的辅助蛋白。在本研究中，研究了第二代HSP 90抑制剂AUY 922在ATLL中的疗效。在体外，AUY 922在HTLV-1感染的T细胞系HUT-102和MT-4中诱导细胞活力的显著抑制。在携带HUT-102异种移植物的免疫缺陷小鼠中，与对照组相比，AUY 922显著延缓肿瘤生长。在苏木精和伊红染色的和末端脱氧核苷酸转移酶脱氧尿苷三磷酸缺口末端标记的AUY 922处理小鼠的组织切片中细胞凋亡是明显的。此外，AUY 922显著降低了替代肿瘤标志物可溶性白细胞介素-2受体和可溶性分化簇30的血清水平。总体而言，本结果证明AUY 922具有有效的抗ATLL活性，从而为在临床试验中继续HSP 90抑制剂的临床开发以治疗ATLL患者提供了理论基础。
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATLL is associated with poor prognosis mainly due to resistance to chemotherapy, which highlights the requirement for alternative therapies. The chaperone heat shock protein (HSP) 90 assist proteins involved in the onset and progression of ATLL. In the present study, the efficacy of a second generation HSP90 inhibitor termed AUY922 was investigated in ATLL. In vitro, AUY922 induced marked inhibition of cell viability in the HTLV-1-infected T-cell lines HUT-102 and MT-4. In immunodeficient mice bearing HUT-102 xenotransplants, AUY922 markedly retarded tumor growth, compared with the control group. Apoptosis was evident in hematoxylin and eosin stained- and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-labeled tissue sections from AUY922-treated mice. In addition, AUY922 significantly reduced the serum levels of the surrogate tumor markers soluble interleukin-2 receptor and soluble cluster of differentiation 30. Overall, the present results demonstrate that AUY922 has potent anti-ATLL activity, thus providing a rationale for continuing the clinical development of HSP90 inhibitors in clinical trials for the treatment of patients with ATLL.