Shiratori Erika, Itoh Mai, Tohda Shuji
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Anticancer Res. 2017 Nov;37(11):6203-6209. doi: 10.21873/anticanres.12070.
BACKGROUND/AIM: Myeloid differentiation primary response gene 88 (MYD88), which activates the nuclear factor kappa B (NF-κB) pathway, is important for the growth of lymphoma and leukaemia cells. In this study, we investigated the effects of ST2825, a synthetic peptidomimetic compound which inhibits MYD88 homodimerization, on their growth.
Seven lymphoma and leukaemia cell lines including TMD8, a B-cell lymphoma line with MYD88-activating mutation, were treated with ST2825 and analysed for cell proliferation and expression of NF-κB signalling-related molecules.
ST2825 suppressed the growth of all cell lines by inducing apoptosis and down-regulating phosphorylation of NF-κB pathway components inhibitor of nuclear factor kappa B kinase (IκB) and reticuloendotheliosis oncogene A (RelA), as well as of MYD88 activator Bruton tyrosine kinase (BTK), suggesting that MYD88 may affect BTK activity. ST2825 effects were specific as MYD88-targeting siRNA also suppressed phosphorylation of NF-κB signalling proteins and BTK in TMD8 cells.
ST2825 may be a novel drug targeting not only B-lymphoid malignancies with MYD88 mutations, but also lymphoma and leukaemia with wild-type MYD88.
背景/目的：髓样分化初级反应基因88（MYD88）可激活核因子κB（NF-κB）信号通路，对淋巴瘤和白血病细胞的生长至关重要。在本研究中，我们研究了抑制MYD88同源二聚化的合成拟肽化合物ST2825对其生长的影响。
用ST2825处理包括TMD8（一种具有MYD88激活突变的B细胞淋巴瘤细胞系）在内的7种淋巴瘤和白血病细胞系，并分析细胞增殖及NF-κB信号相关分子的表达。
ST2825通过诱导凋亡以及下调NF-κB信号通路成分核因子κB激酶抑制剂（IκB）和网状内皮增生症致癌基因A（RelA）以及MYD88激活剂布鲁顿酪氨酸激酶（BTK）的磷酸化，抑制了所有细胞系的生长，这表明MYD88可能影响BTK活性。ST2825的作用具有特异性，因为靶向MYD88的小干扰RNA（siRNA）也抑制了TMD8细胞中NF-κB信号蛋白和BTK的磷酸化。
ST2825可能是一种新型药物，不仅靶向具有MYD88突变的B淋巴细胞恶性肿瘤，还靶向具有野生型MYD88的淋巴瘤和白血病。
