The STAT3 inhibitor WP1066 synergizes with vorinostat to induce apoptosis of mantle cell lymphoma cells
The STAT3 inhibitor WP1066 synergizes with vorinostat to induce apoptosis of mantle cell lymphoma cells
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STAT3抑制剂WP1066与伏立诺他协同诱导套细胞淋巴瘤细胞凋亡
DOI：
10.1016/j.bbrc.2015.06.145
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发表时间：
2015-08-14
影响因子：
3.1
通讯作者：
Wang, Xin
中科院分区：
文献类型：
--
作者：
Lu, Kang;Chen, Na;Wang, Xin
套细胞淋巴瘤（MCL）是以t（11; 14）（q13; q32）易位为特征的侵袭性B细胞非霍奇金淋巴瘤（NHL）。耐药性仍然是治疗的一个巨大障碍，MCL患者的中位生存期为3至5年。因此，迫切需要发现MCL治疗的新方法。已经发现信号转导和转录激活因子3（STAT 3）在MCL细胞系和MCL肿瘤的几种亚型中被组成性激活。WP1066是一种小分子STAT 3抑制剂，通过抑制关键的生存和生长信号通路，在血液和实体恶性肿瘤中发挥抗肿瘤活性。在本研究中，我们评估了WP1066与泛组蛋白脱乙酰酶（HDAC）抑制剂伏立诺他（SAHA）组合在一组MCL细胞系中的抗增殖和促凋亡活性。此外，还探讨了可能的机制。结果表明，WP1066与SAHA在体外联合应用对MCL细胞株具有协同的生长抑制和凋亡诱导作用。此外，WP1066与SAHA的组合抑制了组成性STAT 3激活并调节了抗凋亡基因和促凋亡基因的mRNA表达。我们的研究结果表明，当与SAHA联合使用时，靶向STAT 3通路的药物如WP 1066可能是MCL的有用治疗药物。(C)2015 Elsevier Inc. All rights reserved.
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t (11; 14) (q13; q32). Drug resistance remains a formidable obstacle to treatment and the median survival for MCL patients is between 3 and 5 years. Thus, there is an urgent need to discover novel approaches to MCL therapy. The signal transducer and activation of transcription 3 (STAT3) has been found to be constitutively activated in several subtypes of MCL cell lines and MCL tumors. WP1066, a small-molecule inhibitor of STAT3, exerted antitumor activity in hematological and solid malignancies by inhibiting key survival and growth signaling pathways. In the present study, we evaluated the anti-proliferative and proapoptotic activity of WP1066 combined with pan-histone deacetylase (HDAC) inhibitor vorinostat (SAHA) in a panel of MCL cell lines. In addition, potential mechanisms involved were also explored. The outcome showed that combination of WP1066 with SAHA resulted in synergistic growth inhibition and apoptosis induction in MCL cell lines in vitro. Furthermore, combination of WP1066 with SAHA inhibited the constitutive STAT3 activation and modulated mRNA expressions of anti- and pro-apoptotic genes. Our findings suggest that agents targeting the STAT3 pathway such as WP1066 may be useful therapeutic drugs for MCL when combined with SAHA. (C) 2015 Elsevier Inc. All rights reserved.