双重磷酸肌醇-3 激酶和组蛋白去乙酰化酶抑制剂 CUDC-907 抑制成人 T 细胞白血病增殖的作用。

The role of CUDC-907, a dual phosphoinositide-3 kinase and histone deacetylase inhibitor, in inhibiting proliferation of adult T-cell leukemia.

机构信息

Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.

Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Nishihara, Okinawa, Japan.

出版信息

Eur J Haematol. 2020 Dec;105(6):763-772. doi: 10.1111/ejh.13508. Epub 2020 Sep 3.

DOI:10.1111/ejh.13508

PMID:32780889

Abstract

OBJECTIVES

New effective therapeutic strategies for human T-cell leukemia virus type 1 (HTLV-1)-driven adult T-cell leukemia (ATL) are required because of resistance to chemotherapeutic agents. Here, we aimed to determine the therapeutic efficacy of a dual phosphoinositide 3 kinase (PI3K)/histone deacetylase (HDAC) inhibitor, CUDC-907.

METHODS

Cell viability, cell cycle progression, and apoptotic events were examined by WST-8 assay, flow cytometry, and Hoechst 33342 staining. Caspase activity was determined using Calorimetric Caspase Assay kits. Immunoblotting and electrophoretic mobility shift assay were used to assess the intracellular signaling cascades.

RESULTS

The combination of PI3K inhibitor BKM120 and HDAC inhibitor LBH589 resulted in a synergistic cytotoxic effect in HTLV-1-infected T cells. CUDC-907 was more efficacious than BKM120 and LBH589. It induced G cell cycle arrest with downregulation of cyclin D1/D2, CDK4/6, c-Myc, and phosphorylated retinoblastoma protein expression. Apoptosis was induced via caspase-3/8/9 activation along with downregulation of Bcl-X , Bcl-2, XIAP, survivin, and cIAP1/2, and upregulation of Bax and Bak. Histone H3 acetylation, H2AX activation, Hsp27 phosphorylation, and Hsp70 and Hsp27 upregulation were observed after treatment. CUDC-907 suppressed Akt, NF-κB, and AP-1 by downregulating phosphorylated and/or total Akt, IKKα/β, RelA, JunB, and JunD.

CONCLUSION

CUDC-907 may be a potential therapeutic agent for ATL.

摘要

目的

由于对化疗药物的耐药性，需要寻找新的有效的人类 T 细胞白血病病毒 1（HTLV-1）驱动的成人 T 细胞白血病（ATL）治疗策略。在这里，我们旨在确定双重磷酸肌醇 3 激酶（PI3K）/组蛋白去乙酰化酶（HDAC）抑制剂 CUDC-907 的治疗效果。

方法

通过 WST-8 测定法、流式细胞术和 Hoechst 33342 染色来检测细胞活力、细胞周期进程和凋亡事件。使用比色法半胱天冬酶测定试剂盒来确定半胱天冬酶活性。使用免疫印迹和电泳迁移率变动分析来评估细胞内信号转导途径。

结果

PI3K 抑制剂 BKM120 和 HDAC 抑制剂 LBH589 的联合使用对 HTLV-1 感染的 T 细胞产生协同细胞毒性作用。CUDC-907 比 BKM120 和 LBH589 更有效。它通过下调 cyclin D1/D2、CDK4/6、c-Myc 和磷酸化视网膜母细胞瘤蛋白的表达诱导 G1 期细胞周期停滞。通过 caspase-3/8/9 的激活以及 Bcl-X、Bcl-2、XIAP、survivin 和 cIAP1/2 的下调，以及 Bax 和 Bak 的上调，诱导细胞凋亡。在用 CUDC-907 处理后，观察到组蛋白 H3 乙酰化、H2AX 激活、Hsp27 磷酸化以及 Hsp70 和 Hsp27 的上调。CUDC-907 通过下调磷酸化和/或总 Akt、IKKα/β、RelA、JunB 和 JunD 来抑制 Akt、NF-κB 和 AP-1。