Sorafenib, a multikinase inhibitor, is effective in vitro against non-Hodgkin lymphoma and synergizes with the mTOR inhibitor rapamycin.
Sorafenib, a multikinase inhibitor, is effective in vitro against non-Hodgkin lymphoma and synergizes with the mTOR inhibitor rapamycin.
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DOI：
10.1002/ajh.22263
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发表时间：
2012-03
影响因子：
12.8
通讯作者：
Kumar, Shaji
中科院分区：
文献类型：
--
作者：
Ramakrishnan, Vijay;Timm, Michael;Haug, Jessica L.;Kimlinger, Teresa K.;Halling, Timothy;Wellik, Linda E.;Witzig, Thomas E.;Rajkumar, S. Vincent;Adjei, Alex A.;Kumar, Shaji
非霍奇金淋巴瘤(NHL)是一组起源于淋巴样细胞的异质性肿瘤。血管生成和血管内皮生长因子(VEGF)及其受体(VEGFR)的表达增加与NHL疾病进展有关。血管内皮生长因子和其他细胞因子的增加刺激包括Ras/Raf/MEK/Erk通路在内的信号级联反应，导致细胞增殖增加和细胞凋亡减少。在此，我们报道了VEGFR和Raf激酶的抑制剂索拉非尼的体外抗淋巴瘤活性。索拉非尼对非霍奇金淋巴瘤细胞株和患者样本具有较强的细胞毒作用。这种细胞毒性的诱导与相应的细胞凋亡性增加有关。研究了索拉非尼在滤泡性(DoHH2)和Burkitt淋巴瘤(Raji)细胞系中的作用机制。经索拉非尼处理后，pSTAT3、PACK、MCL1和XIAP在两种细胞系中均下调，而PERK在Raji细胞中降低，而在DoHH2细胞中无明显变化。IL6不能阻止索拉非尼对pStat3、PACK、MCL1和BclxL的抑制。索拉非尼与mTORC1抑制剂雷帕霉素联合应用在诱导NHL细胞毒性方面显示出协同作用。索拉非尼/雷帕霉素联合用药后，PAKT、pMTOR、p-p70S6K、p4EBP1、pGSK3β、mcl1和Bclxl表达下调。根据我们的研究结果，索拉非尼联合伊波利莫治疗NHL患者的临床试验正在进行中。
Non-Hodgkin lymphoma (NHL) represents a heterogenous group of neoplasias originating from lymphoid cells. Increased angiogenesis and expression of Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR) have been found to be associated with NHL disease progression. Increase in VEGF and other cytokines stimulate signaling cascades, including the Ras/Raf/Mek/Erk pathway, resulting in increased proliferation and decreased apoptosis. Here, we report the in vitro antilymphoma activity of sorafenib, an inhibitor of VEGFR and Raf kinase. Sorafenib induced potent cytotoxicity in NHL cell lines and patient samples. This induction of cytotoxicity was associated with a corresponding increase in apoptotic cell death. Mechanism of action of sorafenib was investigated in follicular (DoHH2) and Burkitt lymphoma (Raji) cell lines. pStat3, pAkt, Mcl1, and Xiap were downregulated in both cell lines, whereas pErk decreased in Raji but not in DoHH2 cells following sorafenib treatment. IL6 was unable to prevent sorafenib induced repression of pStat3, pAkt, Mcl1, and Bcl-Xl. Sorafenib in combination with an mTORC1 inhibitor rapamycin demonstrated synergy in inducing cytotoxicity in NHL cells. Sorafenib/rapamycin combination resulted in downregulation of pAkt, pmTOR, p-p70S6K, p4EBP1, pGSK3β, Mcl1, and Bcl-Xl. On the basis of our results, a clinical trial is underway using sorafenib with everolimus in NHL patients.
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影响因子：
20.3
作者：
Gupta, Mamta;Ansell, Stephen M.;Witzig, Thomas E.
通讯作者：
Witzig, Thomas E.
影响因子：
45.3
作者：
Strumberg, D;Richly, H;Seeber, S
通讯作者：
Seeber, S
影响因子：
45.3
作者：
Abou-Alfa, Ghassan K.;Schwartz, Lawrence;Saltz, Leonard B.
通讯作者：
Saltz, Leonard B.
影响因子：
20.3
作者：
Aguayo, A;Kantarjian, H;Albitar, M
通讯作者：
Albitar, M
影响因子：
5
作者：
Gratzinger, Dita;Zhao, Shuchun;Natkunam, Yasodha
通讯作者：
Natkunam, Yasodha