Histone deacetylase inhibitors facilitate dihydroartemisinin-induced apoptosis in liver cancer in vitro and in vivo.
Histone deacetylase inhibitors facilitate dihydroartemisinin-induced apoptosis in liver cancer in vitro and in vivo.
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DOI：
10.1371/journal.pone.0039870
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yun J
中科院分区：
文献类型：
--
作者：
Zhang CZ;Pan Y;Cao Y;Lai PB;Liu L;Chen GG;Yun J
肝癌的患病率和死亡率位居全球前五位癌症之列。越来越多的兴趣集中在开发肝癌治疗的新策略上。我们之前已经证明双氢青蒿素（DHA）对肝癌具有抗肿瘤活性。在这项研究中，我们证明组蛋白脱乙酰酶抑制剂 (HDACi) 通过增加体外和体内细胞凋亡来显着增强 DHA 的抗肿瘤作用。 ERK 磷酸化的抑制有助于 DHA 诱导的细胞凋亡，因为 ERK 磷酸化抑制剂 (PD98059) 会增加 DHA 诱导的细胞凋亡。与单独使用DHA相比，DHA和HDACi联合处理降低了线粒体膜电位，将细胞色素c释放到细胞质中，增加了p53和Bak，减少了Mcl-1和p-ERK，激活了caspase 3和PARP，诱导细胞凋亡。此外，我们发现 HDACi 预处理促进 DHA 诱导的细胞凋亡。在携带Hep G2异种移植瘤的裸鼠中，腹腔注射DHA和SAHA对异种移植瘤有显着的抑制作用。 TUNEL和H&E染色结果显示联合处理诱导更多的细胞凋亡。免疫组织化学数据显示 PARP 激活，Ki-67、p-ERK 和 Mcl-1 减少。综上所述，我们的数据表明 HDACi 和 DHA 的组合对肝癌具有抗肿瘤作用，这种组合治疗应被视为一种有前途的化疗策略。
Liver cancer ranks in prevalence and mortality among top five cancers worldwide. Accumulating interests have been focused in developing new strategies for liver cancer treatment. We have previously showed that dihydroartemisinin (DHA) exhibited antitumor activity towards liver cancer. In this study, we demonstrated that histone deacetylase inhibitors (HDACi) significantly augmented the antineoplastic effect of DHA via increasing apoptosis in vitro and in vivo. Inhibition of ERK phosphorylation contributed to DHA-induced apoptosis, due to the fact that inhibitor of ERK phosphorylation (PD98059) increased DHA-induced apoptosis. Compared with DHA alone, the combined treatment with DHA and HDACi reduced mitochondria membrane potential, released cytochrome c into cytoplasm, increased p53 and Bak, decreased Mcl-1 and p-ERK, activated caspase 3 and PARP, and induced apoptotic cells. Furthermore, we showed that HDACi pretreatment facilitated DHA-induced apoptosis. In Hep G2-xenograft carrying nude mice, the intraperitoneal injection of DHA and SAHA resulted in significant inhibition of xenograft tumors. Results of TUNEL and H&E staining showed more apoptosis induced by combined treatment. Immunohistochemistry data revealed the activation of PARP, and the decrease of Ki-67, p-ERK and Mcl-1. Taken together, our data suggest that the combination of HDACi and DHA offers an antitumor effect on liver cancer, and this combination treatment should be considered as a promising strategy for chemotherapy.
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影响因子：
6.6
作者：
Gould, Justin J.;Kenney, Patrick A.;Summerhayes, Ian C.
通讯作者：
Summerhayes, Ian C.
影响因子：
4.4
作者：
Rahman, Muhammad Shahidur;Yamasaki, Akira;Gounni, Abdelilah Soussi
通讯作者：
Gounni, Abdelilah Soussi
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
5.3
作者：
Chen T;Li M;Zhang R;Wang H
通讯作者：
Wang H
将组蛋白脱乙酰酶抑制剂伏立诺他与极光激酶抑制剂相结合，可通过抑制 c-Myc、hTERT 和 microRNA 水平来增强对淋巴瘤细胞的杀伤作用。
影响因子：
11.2
作者：
Kretzner L;Scuto A;Dino PM;Kowolik CM;Wu J;Ventura P;Jove R;Forman SJ;Yen Y;Kirschbaum MH
通讯作者：
Kirschbaum MH