Inhibition of pan-class I phosphatidyl-inositol-3-kinase by NVP-BKM120 effectively blocks proliferation and induces cell death in diffuse large B-cell lymphoma
Inhibition of pan-class I phosphatidyl-inositol-3-kinase by NVP-BKM120 effectively blocks proliferation and induces cell death in diffuse large B-cell lymphoma
复制标题
DOI：
10.3109/10428194.2013.806800
复制
发表时间：
2014-02
影响因子：
2.6
通讯作者：
C. Zang;J. Eucker;Hongyu Liu;A. Coordes;M. Lenarz;K. Possinger;C. Scholz
中科院分区：
文献类型：
--
作者：
C. Zang;J. Eucker;Hongyu Liu;A. Coordes;M. Lenarz;K. Possinger;C. Scholz
摘要弥漫性大B细胞淋巴瘤（DLBCL）是最常见的侵袭性淋巴瘤，对复发性和难治性疾病的治疗有很大的需求。磷脂酰肌醇-3-激酶（PI 3 K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的组成性激活经常在这种淋巴瘤中检测到。用泛I类PI 3 K抑制剂NVP-BKM 120抑制该信号级联降低了细胞增殖并增加了凋亡性细胞死亡。如果NVP-BKM 120诱导的自噬被阻断，DLBCL增殖进一步降低。用NVP-BKM 120处理与促细胞凋亡的仅BH 3蛋白Puma和Bim的增加以及抗细胞凋亡的Bcl-xL和Mcl-1的下调相关。Bcl-xL和Mcl-1的翻译通过帽依赖性mRNA翻译促进，该过程被NVP-BKM 120部分抑制。总之，我们在此证明了NVP-BKM 120治疗DLBCL的潜力。
Abstract Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive lymphoma, with a great demand for novel treatments for relapsing and refractory disease. Constitutive activation of the phosphatidyl-inositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is often detected in this lymphoma. Inhibition of this signaling cascade with the pan-class I PI3K inhibitor NVP-BKM120 decreased cell proliferation and increased apoptotic cell death. DLBCL proliferation was further decreased if NVP-BKM120-induced autophagy was blocked. Treatment with NVP-BKM120 was associated with an increase of the pro-apoptotic BH3-only proteins Puma and Bim and down-regulation of the anti-apoptotic Bcl-xL and Mcl-1. Translation of Bcl-xL and Mcl-1 is facilitated by cap-dependent mRNA translation, a process that was partially inhibited by NVP-BKM120. Overall, we demonstrated here the potential of NVP-BKM120 for the treatment of DLBCL.