肝癌患病率和死亡率是所有癌症中的前五位，科研界也一直关注于开发治疗肝癌的新策略。青蒿素（artemisinin）是我国科研人员率先从“黄花蒿”中分离提取得到的一种高效低毒抗疟药物。青蒿素内含有独特的过氧化物桥，可以与亚铁离子结合反应形成氧自由基，诱导细胞发生分子损伤和细胞死亡，或通过直接氧化作用损伤细胞的结构和功能，从而导致细胞死亡。
双氢青蒿素（dihydroartemisinin，DHA）是青蒿素药物在体内的主要代谢物，与青蒿素比较，DHA具有水溶性更好，抗疟效力更强的特点。近年来研究表明，双氢青蒿素（DHA）对肝癌具有抗肿瘤活性。
近日PLoS One杂志刊登的一项项研究中，科学家证明，组蛋白去乙酰酶抑制剂（HDACi）通过增加体外和体内肿瘤细胞的凋亡显著增强DHA的抗肿瘤作用。DHA诱导细胞凋亡归因于抑制ERK磷酸化，联用ERK磷酸化抑制剂PD98059能增加DHA诱导凋亡功效。
仅与DHA单用相比， DHA与HDACI综合治疗能降低线粒体膜电位，释放细胞色素c到细胞质中，增加了P53和Bak表达，减少Mcl-1和p-ERK表达，同时caspase3和PARP的活化也增加，这些效应一致诱导肿瘤细胞凋亡。
此外，研究发现HDACI预处理肿瘤细胞有利于DHA诱导细胞凋亡。HepG2细胞裸鼠模型中，腹腔注射DHA和SAHA能显著抑制肿瘤的生长。TUNEL和H＆E染色结果表明联合治疗抑制细胞生长的原因是能诱导肿瘤细胞凋亡。免疫组化数据显示PARP活化，Ki-67、p-ERK和Mcl-1表达下降。
总之数据表明，HDACi和DHA的结合使用可能是一个对肝癌有抗肿瘤作用的非常有前途的治疗策略。（生物谷：Bioon.com)
doi:10.1371/journal.pone.0039870
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Histone Deacetylase Inhibitors Facilitate Dihydroartemisinin-Induced Apoptosis in Liver Cancer In Vitro and In Vivo
Chris Zhiyi Zhang, Yinghua Pan, Yun Cao, Paul B. S. Lai, Lili Liu, George Gong Chen*, Jingping Yun*
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.
