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

作者：Chuanbing Zang, Jan Eucker, Hongyu Liu, Annekatrin Coordes, Minoo Lenarz, Kurt Possinger, Christian Schölz · 发表于：Leukemia & lymphoma/Leukemia and lymphoma · 年份：2013 · DOI：10.3109/10428194.2013.806800 · 被引用次数：50 · 研究领域：Autophagy in Disease and Therapy、Chronic Lymphocytic Leukemia Research、Ubiquitin and proteasome pathways

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.