title: Synergistic antitumor activity of oridonin and arsenic trioxide on hepatocellular             carcinoma cells.
abstract: Although arsenic trioxide (As2O3) has been successfully employed in treatment             of patients with APL (acute promyelocytic leukemia), the sensitivity of solid             tumor cells to this treatment was much lower than APL cells. The single agent             of As2O3 was inefficient for treatment of hepatocellular carcinoma (HCC) in phase             II trial demonstrating that new modalities of treatment with enhanced therapeutic             effect are needed. In this study, we showed that oridonin, a diterpenoid isolated             from traditional Chinese medicine Rabdosia rubescences, greatly potentiated apoptosis             induced by As2O3 in hepatocellular carcinoma cells. The synergistic pro-apoptosis             effect of combination of these two drugs led to increase in intracellular reactive             oxygen species (ROS) level and N-acetyl-L-cysteine (NAC), a thiol-containing anti-oxidant,             was able to completely block the effect. The combination treatment induced ROS-dependent             decrease in mitochondrial membrane potential (MMP) decrease, and relocation of             Bax and cytochrome C. Besides, oridonin dramatically increased the intracellular             Ca2+ overload triggered by As2O3. Furthermore, the co-treatment of oridonin and             As2O3 induced ROS-mediated down-regulation of Akt and XIAP, and inhibition of             NF-κB activation. The two drug combination enhanced tumor suppression activity             in murine HCC model compared with single agent treatment in vivo. These findings             demonstrate that oridonin can sensitize hepatocellular carcinoma cells to As2O3             treatment and will facilitate the optimization of As2O3 therapy for HCC patients.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology and                     Department of Biochemistry, College of Life Sciences, Nanjing University,                     Nanjing 210093, P.R. China.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Bing-Ya
authors.initials: BY
authors.lastname: Yang
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.forename: Jian-Xiang
authors.initials: JX
authors.lastname: Chen
authors.forename: Zi-Chun
authors.initials: ZC
authors.lastname: Hua
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D045786:Diterpenes, Kaurane / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009368:Neoplasm Transplantation; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001152:Arsenicals; D045786:Diterpenes, Kaurane; D016328:NF-kappa B; D010087:Oxides; D017382:Reactive Oxygen Species; D051636:X-Linked Inhibitor of Apoptosis Protein; C011959:oridonin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide