HDAC inhibitor L-carnitine and proteasome inhibitor bortezomib synergistically exert anti-tumor activity in vitro and in vivo.
HDAC inhibitor L-carnitine and proteasome inhibitor bortezomib synergistically exert anti-tumor activity in vitro and in vivo.
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HDAC 抑制剂左旋肉碱和蛋白酶体抑制剂硼替佐米在体外和体内协同发挥抗肿瘤活性
DOI：
10.1371/journal.pone.0052576
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Huang H;Liu N;Yang C;Liao S;Guo H;Zhao K;Li X;Liu S;Guan L;Liu C;Xu L;Zhang C;Song W;Li B;Tang P;Dou QP;Liu J
在临床前试验中，蛋白酶体抑制剂和组蛋白脱乙酰酶(HDAC)抑制剂的组合似乎最能产生协同细胞毒性。我们最近证实L肉碱(LC)是一种内源性的HDAC抑制剂。在本研究中，我们观察了LC联合蛋白酶体抑制剂Bortezomib(VELCADE，VEL)对培养的肝癌细胞和荷HepG2肿瘤的Balb/c小鼠的抗肿瘤作用。流式细胞仪检测细胞死亡，MTS法检测细胞存活率。基因芯片检测基因表达，实时定量聚合酶链式反应检测基因表达，Western印迹检测蛋白表达水平。用芯片技术检测VEL对p21cip1基因启动子相关的组蛋白H3乙酰化的影响，用细胞胰凝乳酶样活性测定检测蛋白酶体多肽酶活性。在这里，我们报道：(I)LC和VEL在体外协同诱导细胞毒作用；(Ii)在体内，LC和VEL还协同抑制肿瘤生长；(Iii)联合治疗的协同作用涉及两个主要途径：增加p21cip1的表达和体内和体内的组蛋白乙酰化，以及LC增强VEL诱导的蛋白酶体抑制。LC和VEL在肿瘤治疗中的协同作用在未来的临床试验中应该有很大的潜力。
Combinations of proteasome inhibitors and histone deacetylases (HDAC) inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC) is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel) was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by flow cytometry and MTS, respectively. Gene, mRNA expression and protein levels were detected by gene microarray, quantitative real-time PCR and Western blot, respectively. The effect of Vel on the acetylation of histone H3 associated with the p21cip1 gene promoter was examined by using ChIP assay and proteasome peptidase activity was detected by cell-based chymotrypsin-like (CT-like) activity assay. Here we report that (i) the combination of LC and Vel synergistically induces cytotoxicity in vitro; (ii) the combination also synergistically inhibits tumor growth in vivo; (iii) two major pathways are involved in the synergistical effects of the combinational treatment: increased p21cip1 expression and histone acetylation in vitro and in vivo and enhanced Vel-induced proteasome inhibition by LC. The synergistic effect of LC and Vel in cancer therapy should have great potential in the future clinical trials.
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P21（WAF1/CIP1）通过应力颗粒相关的蛋白CUGBP1上调赋予对硼替佐米介导的凋亡的抗性。
影响因子：
3.7
作者：
Gareau C;Fournier MJ;Filion C;Coudert L;Martel D;Labelle Y;Mazroui R
通讯作者：
Mazroui R
DOI：
10.1158/1078-0432.ccr-10-1878
发表时间：
2011-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Lancet JE;Duong VH;Winton EF;Stuart RK;Burton M;Zhang S;Cubitt C;Blaskovich MA;Wright JJ;Sebti S;Sullivan DM
通讯作者：
Sullivan DM
L-肉碱是一种内源性 HDAC 抑制剂，可选择性抑制体内和体外癌细胞生长
影响因子：
3.7
作者：
Huang H;Liu N;Guo H;Liao S;Li X;Yang C;Liu S;Song W;Liu C;Guan L;Li B;Xu L;Zhang C;Wang X;Dou QP;Liu J
通讯作者：
Liu J
影响因子：
5.7
作者：
Kim J;Guan J;Chang I;Chen X;Han D;Wang CY
通讯作者：
Wang CY
Vorinostat与Bortezomib结合的I阶段研究，用于复发和难治性多发性骨髓瘤。
影响因子：
11.5
作者：
Badros, Ashraf;Burger, Angelika M.;Philip, Sunita;Niesvizky, Ruben;Kolla, Sarah S.;Goloubeva, Olga;Harris, Carolynn;Zwiebel, James;Wright, John J.;Espinoza-Delgado, Igor;Baer, Maria R.;Holleran, Julianne L.;Egorin, Merrill J.;Grant, Steven
通讯作者：
Grant, Steven