肝癌患病率和死亡率是所有癌癥中的前五位,，科研界也一直關注于開發(fā)治療肝癌的新策略,。青蒿素（artemisinin）是我國科研人員率先從“黃花蒿”中分離提取得到的一種高效低毒抗瘧藥物。青蒿素內含有獨特的過氧化物橋,，可以與亞鐵離子結合反應形成氧自由基,，誘導細胞發(fā)生分子損傷和細胞死亡，或通過直接氧化作用損傷細胞的結構和功能,，從而導致細胞死亡,。
雙氫青蒿素（dihydroartemisinin，DHA）是青蒿素藥物在體內的主要代謝物,，與青蒿素比較,，DHA具有水溶性更好，抗瘧效力更強的特點,。近年來研究表明,，雙氫青蒿素（DHA）對肝癌具有抗腫瘤活性,。
近日PLoS One雜志刊登的一項項研究中，科學家證明,，組蛋白去乙酰酶抑制劑（HDACi）通過增加體外和體內腫瘤細胞的凋亡顯著增強DHA的抗腫瘤作用,。DHA誘導細胞凋亡歸因于抑制ERK磷酸化，聯(lián)用ERK磷酸化抑制劑PD98059能增加DHA誘導凋亡功效,。
僅與DHA單用相比,， DHA與HDACI綜合治療能降低線粒體膜電位，釋放細胞色素c到細胞質中,，增加了P53和Bak表達,，減少Mcl-1和p-ERK表達，同時caspase3和PARP的活化也增加,，這些效應一致誘導腫瘤細胞凋亡,。
此外,，研究發(fā)現(xiàn)HDACI預處理腫瘤細胞有利于DHA誘導細胞凋亡,。HepG2細胞裸鼠模型中，腹腔注射DHA和SAHA能顯著抑制腫瘤的生長,。TUNEL和H＆E染色結果表明聯(lián)合治療抑制細胞生長的原因是能誘導腫瘤細胞凋亡,。免疫組化數(shù)據(jù)顯示PARP活化，Ki-67,、p-ERK和Mcl-1表達下降,。
總之數(shù)據(jù)表明，HDACi和DHA的結合使用可能是一個對肝癌有抗腫瘤作用的非常有前途的治療策略,。（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.
