Tsai Hui-Jen, Shih Neng-Yao, Kuo Sung-Hsin, Cheng Ann-Lii, Lin Hui-You, Chen Tsai-Yun, Chang Kung-Chao, Lin Sheng-Fung, Chang Jeffrey S, Chen Li-Tzong
a National Institute of Cancer Research, National Health Research Institutes , Tainan , Taiwan.
b Division of Hematology/Oncology, Department of Internal Medicine , National Cheng Kung University Hospital , Tainan , Taiwan.
Leuk Lymphoma. 2015;56(9):2674-82. doi: 10.3109/10428194.2014.995647. Epub 2015 Jan 21.
Recurrent genetic alterations that are frequently observed in some low-grade lymphomas, such as activated B cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL) and mucosa-associated lymphoid tissue type lymphoma (MALT lymphoma) are usually associated with nuclear factor-κB (NF-κB) activation and confer resistance to therapy. In this study, we investigated the therapeutic efficacy and molecular mechanisms of AUY922, a novel Hsp90 inhibitor, in representative cell lines OCI-Ly3 (ABC-DLBCL) and MA-1 (a low-grade lymphoma cell line with t(14;18)/IgH-MALT1translocation) to explore its potential use in the treatment of refractory B-cell lymphoma. Our results showed that AUY922 effectively induced growth inhibition and apoptosis of OCI-Ly3 and MA-1 cells, which were accompanied by down-regulation of the expression levels of NF-κB and Bcl-2 family proteins, as well as molecules of multiple signaling pathways involving cell proliferation, growth and survival. The growth inhibitory effect of AUY922 was further confirmed in a mouse xenograft model. These findings indicate the potential use of AUY922 in B cell lymphomas.
在一些低级别淋巴瘤中经常观察到的复发性基因改变，如弥漫性大B细胞淋巴瘤的活化B细胞亚型（ABC-DLBCL）和黏膜相关淋巴组织型淋巴瘤（MALT淋巴瘤），通常与核因子-κB（NF-κB）激活相关，并赋予对治疗的抗性。在本研究中，我们研究了新型Hsp90抑制剂AUY922在代表性细胞系OCI-Ly3（ABC-DLBCL）和MA-1（具有t(14;18)/IgH-MALT1易位的低级别淋巴瘤细胞系）中的治疗效果和分子机制，以探索其在难治性B细胞淋巴瘤治疗中的潜在用途。我们的结果表明，AUY922有效诱导OCI-Ly3和MA-1细胞的生长抑制和凋亡，这伴随着NF-κB和Bcl-2家族蛋白表达水平的下调，以及涉及细胞增殖、生长和存活的多个信号通路分子的下调。AUY922的生长抑制作用在小鼠异种移植模型中得到进一步证实。这些发现表明AUY922在B细胞淋巴瘤中有潜在用途。
