Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor ACY-1215 and Bortezomib Is Synergistic in Lymphoma.
Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor ACY-1215 and Bortezomib Is Synergistic in Lymphoma.
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DOI：
10.1158/1078-0432.ccr-14-3068
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发表时间：
2015-10-15
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影响因子：
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通讯作者：
O'Connor OA
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作者：
Amengual JE;Johannet P;Lombardo M;Zullo K;Hoehn D;Bhagat G;Scotto L;Jirau-Serrano X;Radeski D;Heinen J;Jiang H;Cremers S;Zhang Y;Jones S;O'Connor OA
泛类组蛋白去乙酰化酶（HDAC）抑制剂是有效的治疗选择淋巴瘤。异构体选择性HDAC抑制剂正在成为潜在的更具靶向的药物。HDAC 6是IIb类脱乙酰酶，其促进错误折叠的蛋白质转运至攻击体以进行降解。我们研究了选择性HDAC 6抑制剂ACY-1215单独使用和与硼替佐米联合使用在淋巴瘤临床前模型中的机制和治疗效果。定义ACY-1215在16种淋巴瘤细胞系中的浓度：效应关系以及与硼替佐米的协同作用。通过免疫印迹和流式细胞术研究机制。DLBCL的体内异种移植模型用于确认体外发现。调查了一组原发性淋巴瘤样本的UPR标志物。浓度：效应关系定义了48小时时的最大细胞毒性，IC 50值范围为0.9-4.7 μM。与硼替佐米组合时观察到强协同作用。用ACY-1215处理导致由乙酰化α-微管蛋白和积累的多聚泛素化蛋白质证明的侵袭组的抑制，以及UPR的上调。所有的药效学作用都随着硼替佐米的加入而增强。结果在体内得到了验证，其中用该组合治疗的小鼠表现出显著的肿瘤生长延迟和延长的总生存期。对一组原发性淋巴瘤样品的UPR标志物的评价显示，与反应性淋巴组织相比，HDAC 6、GRP 78和XBP-1表达增加。这些数据是证明蛋白质降解途径的双重靶向是治疗淋巴瘤的创新和合理方法的第一个结果。
Pan-class histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform selective HDAC inhibitors are emerging as potentially more targeted agents. HDAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for degradation. We investigated the mechanism and therapeutic impact of the selective HDAC6 inhibitor ACY-1215 alone and in combination with bortezomib in preclinical models of lymphoma. Concentration : effect relationships were defined for ACY-1215 across 16 lymphoma cell lines and for synergy with bortezomib. Mechanism was interrogated by immunoblot and flow cytometry. An in vivo xenograft model of DLBCL was utilized to confirm in vitro findings. A collection of primary lymphoma samples were surveyed for markers of the UPR. Concentration : effect relationships defined maximal cytotoxicity at 48 hours with IC50 values ranging from 0.9—4.7 μM. Strong synergy was observed in combination with bortezomib. Treatment with ACY-1215 led to inhibition of the aggresome evidenced by acetylated α-tubulin and accumulated poly-ubiquitinated proteins, and up-regulation of the UPR. All pharmacodynamic effects were enhanced with the addition of bortezomib. Findings were validated in vivo where mice treated with the combination demonstrated significant tumor growth delay and prolonged overall survival. Evaluation of a collection of primary lymphoma samples for markers of the UPR revealed increased HDAC6, GRP78 and XBP-1 expression as compared to reactive lymphoid tissue. These data are the first results to demonstrate that dual targeting of protein degradation pathways represents an innovative and rational approach for the treatment of lymphoma.