mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells.
mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells.
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DOI：
10.18632/oncotarget.2992
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发表时间：
2015-02-10
期刊：
影响因子：
--
通讯作者：
Fruman DA
中科院分区：
文献类型：
--
作者：
Beagle BR;Nguyen DM;Mallya S;Tang SS;Lu M;Zeng Z;Konopleva M;Vo TT;Fruman DA
雷帕霉素机制靶点（mTOR）的高活性与前B细胞急性淋巴细胞白血病（B-ALL）的不良预后相关，表明抑制mTOR可能在临床上有用。然而，新出现的数据表明，mTOR抑制剂与其他靶向药物联合使用时最有效。一种策略是将联合收割机与组蛋白脱乙酰酶（HDAC）抑制剂联合使用，因为B-ALL通常以沉默促凋亡因子表达的表观遗传学变化为特征。在这里，我们测试了mTOR和泛HDAC抑制剂对B-ALL细胞的组合，包括费城染色体阳性（Ph+）和非Ph细胞系。我们发现，mTOR激酶抑制剂（TOR-KIs）与HDAC抑制剂协同作用，导致B-ALL细胞凋亡，与雷帕霉素加HDAC抑制剂相比，效果更大。TOR-KI与临床批准的HDAC抑制剂伏立诺他的组合增加了体外原代儿科B-ALL细胞的凋亡。从机制上讲，TOR-KI和HDAC抑制剂组合增加了促死亡基因的表达，包括叉头盒0（FOXO）转录因子的靶标，并增加了对线粒体处的凋亡触发物的敏感性。这些发现表明，靶向表观遗传因子可以揭示TOR-KI对B-ALL细胞的细胞毒性潜力。
High activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis in pre-B-cell acute lymphoblastic leukemia (B-ALL), suggesting that inhibiting mTOR might be clinically useful. However, emerging data indicate that mTOR inhibitors are most effective when combined with other target agents. One strategy is to combine with histone deacetylase (HDAC) inhibitors, since B-ALL is often characterized by epigenetic changes that silence the expression of pro-apoptotic factors. Here we tested combinations of mTOR and pan-HDAC inhibitors on B-ALL cells, including both Philadelphia chromosome-positive (Ph+) and non-Ph cell lines. We found that mTOR kinase inhibitors (TOR-KIs) synergize with HDAC inhibitors to cause apoptosis in B-ALL cells and the effect is greater when compared to rapamycin plus HDAC inhibitors. The combination of TOR-KIs with the clinically approved HDAC inhibitor vorinostat increased apoptosis in primary pediatric B-ALL cells in vitro. Mechanistically, TOR-KI and HDAC inhibitor combinations increased expression of pro-death genes, including targets of the Forkhead Box O (FOXO) transcription factors, and increased sensitivity to apoptotic triggers at the mitochondria. These findings suggest that targeting epigenetic factors can unmask the cytotoxic potential of TOR-KIs towards B-ALL cells.
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影响因子：
82.9
作者：
Janes, Matthew R.;Limon, Jose J.;So, Lomon;Chen, Jing;Lim, Raymond J.;Chavez, Melissa A.;Vu, Collin;Lilly, Michael B.;Mallya, Sharmila;Ong, S. Tiong;Konopleva, Marina;Martin, Michael B.;Ren, Pingda;Liu, Yi;Rommel, Christian;Fruman, David A.
通讯作者：
Fruman, David A.
影响因子：
7.3
作者：
Bean GR;Ganesan YT;Dong Y;Takeda S;Liu H;Chan PM;Huang Y;Chodosh LA;Zambetti GP;Hsieh JJ;Cheng EH
通讯作者：
Cheng EH
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：
8
作者：
Essafi, A;de Mattos, SF;Lam, EWF
通讯作者：
Lam, EWF
DOI：
10.1126/science.1199498
发表时间：
2011-06-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hsu PP;Kang SA;Rameseder J;Zhang Y;Ottina KA;Lim D;Peterson TR;Choi Y;Gray NS;Yaffe MB;Marto JA;Sabatini DM
通讯作者：
Sabatini DM