title: Dihydroartemisinin exhibits antitumor activity toward hepatocellular carcinoma in vitro and in vivo.
abstract: Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin isolated from the traditional Chinese herb Artemisia annua L., has been shown to exhibit inhibitory effects on human cancer cells. However, its antitumor ability toward hepatocellular carcinoma (HCC) has not been studied. In this study, we demonstrated that DHA significantly inhibited HCC cell growth in vitro and in vivo via inducing G2/M cell cycle arrest and apoptosis. The induction of p21 and the inhibition of cyclin B and CDC25C contributed to DHA-induced G2/M arrest. DHA-induced apoptosis was associated with mitochondrial membrane depolarization, release of cytochrome c, activation of caspases, and DNA fragmentation. Activation of caspase 9 and caspase 3, but not caspase 8, was detected in DHA-treated cells. Attenuation of apoptosis in cells pretreated with Z-VAD-FMK suggested the involvement of caspase cascade. Furthermore, p53 facilitated apoptosis caused by DHA. Bcl-2 family proteins were also responsible for DHA-induced apoptosis. DHA exposure decreased Mcl-1 expression but increased the levels of Noxa and active Bak. Bak was released from the Mcl-1/Bak complex due to the decline of Mcl-1. Further study revealed that Mcl-1 was rapidly degraded in DHA-treated cells and that DHA-induced apoptosis was largely inhibited by overexpression of Mcl-1 or RNAi-mediated decrease of Bak and Noxa. In a HCC-xenograft mouse model, the intraperitoneal injection of DHA resulted in significant inhibition of HCC xenograft tumors. Taken together, our data, for the first time, demonstrate the potential antitumor activity of DHA in HCC.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Chris Zhiyi
authors.initials: CZ
authors.lastname: Zhang
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Jingping
authors.initials: J
authors.lastname: Yun
authors.forename: George Gong
authors.initials: GG
authors.lastname: Chen
authors.forename: Paul Bo San
authors.initials: PB
authors.lastname: Lai
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D016158:Genes, p53; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D037621:Artemisinins; C494772:BAK1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; C039060:artenimol; D045304:Cytochromes c; D020169:Caspases