Targeting survival and cell trafficking in multiple myeloma and Waldenstrom macroglobulinemia using pan-class I PI3K inhibitor, buparlisib.
Targeting survival and cell trafficking in multiple myeloma and Waldenstrom macroglobulinemia using pan-class I PI3K inhibitor, buparlisib.
复制标题
使用泛 I 类 PI3K 抑制剂 buparlisib 靶向多发性骨髓瘤和华氏巨球蛋白血症的存活和细胞运输。
DOI：
10.1002/ajh.23814
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发表时间：
2014
影响因子：
12.8
通讯作者：
Ghobrial,IreneM
中科院分区：
文献类型：
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作者：
Sahin,Ilyas;Azab,Feda;Mishima,Yuji;Moschetta,Michele;Tsang,Brian;Glavey,SiobhanV;Manier,Salomon;Zhang,Yu;Sacco,Antonio;Roccaro,AldoM;Azab,AbdelKareem;Ghobrial,IreneM
磷脂酰肌醇3激酶（PI3K）通路在多发性骨髓瘤（MM）和Waldenstrom Macroglobulenima （WM）中被激活，并在肿瘤进展和耐药中起关键作用。在这项研究中，我们描述了泛I类PI3K抑制对MM和WM细胞运输和存活的作用。我们测试了siRNA沉默或布帕利西布药物抑制pan - I类PI3K对体外MM细胞存活、凋亡和细胞周期的影响，以及体内MM细胞的肿瘤生长和动员的影响。然后，我们评估了buparisib依赖性诱导MM细胞动员的机制。此外，研究人员还评估了布帕利西布对WM细胞存活、凋亡和与骨髓基质细胞（BMSCs）粘附的影响。我们发现布帕利西布在MM细胞中诱导毒性，并通过诱导细胞凋亡和细胞周期阻滞来支持。布帕利西布也被发现在体内减少肿瘤进展。重要的是，buparisib增强了MM细胞在体内的动员，这是由MM细胞对BMSCs的粘附减少和通过上调CXCR4表达而增加的趋化性驱动的。与对MM细胞的作用类似，布帕利西布也能诱导细胞存活和凋亡，并降低WM细胞的粘附。这些数据强调了I类PI3K信号在B细胞恶性肿瘤存活和细胞传播调控中的重要作用。点。中华血液学杂志，2014,32(1):444 - 444。©2014 Wiley期刊公司
The phosphatidylinositol‐3 kinase (PI3K) pathway is activated in multiple myeloma (MM) and Waldenstrom Macroglobulenima (WM), and plays a crucial role in tumor progression and drug resistance. In this study, we characterized the role of pan‐class I PI3K inhibition on cell trafficking and survival of MM and WM cells. We tested the effect of pan‐class I PI3K inhibition by siRNA silencing or pharmacologic inhibition with buparlisib on MM cell survival, apoptosis and cell cycle in vitro and tumor growth and mobilization of MM cells in vivo. We then evaluated buparlisib‐dependent mechanisms of induced MM cell mobilization. Moreover, the effect of buparlisib on cell survival, apoptosis, and adhesion of WM cells to bone marrow stromal cells (BMSCs) has been evaluated. We showed that buparlisib induced toxicity in MM cells, supported by induction of apoptosis and cell cycle arrest. Buparlisib was also found to reduce tumor progression in vivo. Importantly, buparlisib enhanced MM cell mobilization in vivo which was driven by decreased adhesion of MM cells to BMSCs and increased chemotaxis via up‐regulation of CXCR4 expression. Similar to its effects on MM cells, buparlisib also induced cell survival and apoptosis, and decreased adhesion in WM cells. These data highlight the critical contribution of class I PI3K signaling to the regulation of survival and cell dissemination in B‐cell malignancies. Am. J. Hematol. 89:1030–1036, 2014. © 2014 Wiley Periodicals, Inc.