title: NG, a novel PABA/NO-based oleanolic acid derivative, induces human hepatoma cell apoptosis via a ROS/MAPK-dependent mitochondrial pathway.
abstract: O(2)-(2,4-dinitro-5-{[2-(12-en-28-β-D- galactopyranosyl-oleanolate-3-yl) -oxy-2-oxoethyl]amino}phenyl)1-(N-hydroxyethylmethylamino)diazen-1-ium-1,2- diolate (NG), a novel PABA/NO-based derivative of oleanolic acid (OA), has been found to show potent antitumor activity both in vivo and in vitro. In the present study, NG could significantly reduce tumor volume and weight in the H22 solid tumor mouse model. Meanwhile, NG showed selective effects on the HepG2 cells including NO generation, cytotoxic effect and apoptosis, which were prevented by hemoglobin (NO scavenger). Moreover, NG-induced apoptosis of HepG2 cells was characteristic of intracellular reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential (Δψm) and enhanced Bax-to-Bcl-2 ratio. The release of apoptotic inducing factor (AIF) and cytochrome c (Cyt c) from mitochondria and the activation of caspase-3, 9 were also detected, indicating that NG may induce apoptosis through a mitochondrial-mediated pathway. Simultaneously, NG treatment could lead to the activation of the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK but not ERK1/2. Treatment with SP600125 (an inhibitor of JNK) and SB203580 (an inhibitor of p38) prior to NG was found to reverse NG-induced apoptosis. Moreover, it was found that antioxidant N-acetylcysteine (NAC) blocked the induction of apoptosis and partly reversed the activation of JNK and p38, up-regulation of Bax, down-regulation of Bcl-2 and the activation of caspase-3 in NG-treated cells. Taking together, these findings suggest that NO can be released from NG, which induces apoptosis through a ROS/MAPK-mediated mitochondrial pathway.
authors: State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors: Ling
authors: L
authors: Liu
authors: Junjie
authors: J
authors: Fu
authors: Tingting
authors: T
authors: Li
authors: Ran
authors: R
authors: Cui
authors: Jingjing
authors: J
authors: Ling
authors: Xing
authors: X
authors: Yu
authors: Hui
authors: H
authors: Ji
authors: Yihua
authors: Y
authors: Zhang
mesh_terms: D010129:4-Aminobenzoic Acid / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001391:Azo Compounds / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000737:chemistry*; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012503:Saponins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; C576900:O2-(2,4-dinitro-5-((2-(12-en-28-galactopyranosyloleanolate-3-yl)oxy-2-oxoethyl)amino)phenyl) 1-(N-hydroxyethylmethylamino)diazen-1-ium-1,2-diolate; D017382:Reactive Oxygen Species; D012503:Saponins; D009569:Nitric Oxide; D009828:Oleanolic Acid; D010129:4-Aminobenzoic Acid