Silvestrol exhibits significant in vivo and in vitro antileukemic activities and inhibits FLT3 and miR-155 expressions in acute myeloid leukemia.
Silvestrol exhibits significant in vivo and in vitro antileukemic activities and inhibits FLT3 and miR-155 expressions in acute myeloid leukemia.
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DOI：
10.1186/1756-8722-6-21
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发表时间：
2013-03-16
影响因子：
28.5
通讯作者：
Marcucci G
中科院分区：
文献类型：
--
作者：
Alachkar H;Santhanam R;Harb JG;Lucas DM;Oaks JJ;Hickey CJ;Pan L;Kinghorn AD;Caligiuri MA;Perrotti D;Byrd JC;Garzon R;Grever MR;Marcucci G
激活突变[内部串联重复（ITD）]或FMS样酪氨酸激酶受体-3（FLT 3）基因的过表达与急性髓性白血病（AML）患者的不良结局相关，强调了对新治疗方法的需求。天然产物司维司群在几种恶性肿瘤中具有有效的抗肿瘤活性，但其对不同分子高危AML亚群的治疗作用仍有待充分研究。我们在此检查了司维司群在FLT 3-ITD和FLT 3野生型（wt）AML中的临床前活性。通过比色法细胞活力测定、集落形成和流式细胞术测定分别评估生长抑制和细胞凋亡来检查司维司群的体外抗白血病活性。分别通过RNA免疫沉淀、qRT-PCR和免疫印迹分析测定了司维司群对FLT 3 mRNA翻译、mRNA和蛋白表达的药理活性。使用MV 4 -11白血病移植小鼠研究了司维司群的体内功效。纳摩尔浓度的司维司群在表达FLT 3-wt的AML细胞系（THP-1）和表达FLT 3-ITD的AML细胞系（MV 4 -11）（IC 50分别为3.8和2.7 nM）和患者的原代母细胞中均显示出抗白血病活性[IC 50 = ~12 nM（FLT 3-wt）和~5 nM（FLT 3-ITD）]。在原代母细胞中，司维司群增加凋亡（~ 4倍，P = 0.0001），并抑制集落形成（100%，P < 0.0001）。司维司群有效抑制FLT 3翻译，使FLT 3蛋白表达降低80-90%，并降低miR-155水平（约60%），miR-155是FLT 3-ITD阳性AML中常见的共调节癌miR。植入后，司维司群处理的小鼠与赋形剂处理的小鼠的中位生存期分别为63天与29天（P < 0.0001）。通过抑制FLT 3和miR-155表达的新机制，司维司群在AML中表现出显著的体内和体外抗白血病活性。这些令人鼓舞的结果保证了快速翻译的silvestrol在AML的临床试验。
Activating mutations [internal tandem duplication (ITD)] or overexpression of the FMS-like tyrosine kinase receptor-3 (FLT3) gene are associated with poor outcome in acute myeloid leukemia (AML) patients, underscoring the need for novel therapeutic approaches. The natural product silvestrol has potent antitumor activity in several malignancies, but its therapeutic impact on distinct molecular high-risk AML subsets remains to be fully investigated. We examined here the preclinical activity of silvestrol in FLT3-ITD and FLT3 wild-type (wt) AML. Silvestrol in vitro anti-leukemic activity was examined by colorimetric cell viability assay, colony-forming and flow cytometry assays assessing growth inhibition and apoptosis, respectively. Pharmacological activity of silvestrol on FLT3 mRNA translation, mRNA and protein expression was determined by RNA-immunoprecipitation, qRT-PCR and immunoblot analyses, respectively. Silvestrol in vivo efficacy was investigated using MV4-11 leukemia-engrafted mice. Silvestrol shows antileukemia activity at nanomolar concentrations both in FLT3-wt overexpressing (THP-1) and FLT3-ITD (MV4-11) expressing AML cell lines (IC50 = 3.8 and 2.7 nM, respectively) and patients’ primary blasts [IC50 = ~12 nM (FLT3-wt) and ~5 nM (FLT3-ITD)]. Silvestrol increased apoptosis (~4fold, P = 0.0001), and inhibited colony-formation (100%, P < 0.0001) in primary blasts. Silvestrol efficiently inhibited FLT3 translation reducing FLT3 protein expression by 80–90% and decreased miR-155 levels (~60%), a frequently co-regulated onco-miR in FLT3-ITD-positive AML. The median survival of silvestrol-treated vs vehicle-treated mice was 63 vs 29 days post-engraftment, respectively (P < 0.0001). Silvestrol exhibits significant in vivo and in vitro antileukemic activities in AML through a novel mechanism resulting in inhibition of FLT3 and miR-155 expression. These encouraging results warrant a rapid translation of silvestrol for clinical testing in AML.
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影响因子：
28.5
作者：
Faraoni I;Laterza S;Ardiri D;Ciardi C;Fazi F;Lo-Coco F
通讯作者：
Lo-Coco F
影响因子：
20.3
作者：
Guzman, ML;Neering, SJ;Jordan, CT
通讯作者：
Jordan, CT
影响因子：
3.6
作者：
Hwang, BY;Su, BN;Kinghorn, AD
通讯作者：
Kinghorn, AD
影响因子：
20.3
作者：
Kottaridis, PD;Gale, RE;Linch, DC
通讯作者：
Linch, DC
影响因子：
3.2
作者：
Garzon, Ramiro;Croce, Carlo M.
通讯作者：
Croce, Carlo M.