title: ZL11n is a novel nitric oxide-releasing derivative of farnesylthiosalicylic acid that induces apoptosis in human hepatoma HepG2 cells via MAPK/mitochondrial pathways.
abstract: ZL11n is a novel furoxan-based nitric oxide (NO)-releasing derivative of farnesylthiosalicylic acid. In this study, we examined the anticancer effects and the potential mechanism of action of ZL11n in vitro and in vivo. It was found that ZL11n exhibited a favorable, selective cytotoxic effect in the HepG2 cell line. The yield of NO in the ZL11n treated HepG2 cells was much higher than in the control group and the normal human liver L-02 cells. Furthermore, the NO concentration was correlated to the degree of cytotoxicity observed. The ZL11n-induced apoptosis was assessed by Annexin V-FITC/propidium iodide flow cytometry assay. ZL11n triggered the mitochondrial/caspase apoptotic pathway by decreasing mitochondrial membrane potential, cytochrome c release from mitochondrial, and reducing the Bcl-2-to-Bax ratio, in addition to activating the caspase cascade. Simultaneously, we found that ZL11n treatment led to an increase in JNK and ERK1/2 phosphorylation. Furthermore, treatment with SP600125 (a JNK inhibitor) and PD98059 (an ERK1/2 inhibitor) prior to ZL11n treatment was found to significantly reverse ZL11n-induced apoptosis. The in vivo findings also revealed that ZL11n significantly reduced tumor volume and weight in the H(22) solid tumor mouse model examined. In short, our findings suggest that ZL11n induced apoptosis through the coordination of the mitochondrial apoptotic pathway (activated by NO) and MAPKs signaling pathway (triggered by JNK or ERK).
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Ling
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Jianxin
authors.initials: J
authors.lastname: Tang
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005204:Farnesol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010069:Oxadiazoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012459:Salicylates / Q000737:chemistry
chemical_list: C560757:3-(phenylsulfonyl)-4-(4-(1-(2-(3,7,11-trimethyldodeca-2,6,10-trienylthio)benzoyl)pyrrolidine-2-carbonyloxy)but-2-ynyloxy)-1,2,5-oxadiazole-2-oxide; D000970:Antineoplastic Agents; D010069:Oxadiazoles; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D009569:Nitric Oxide; D005204:Farnesol; D020929:Mitogen-Activated Protein Kinase Kinases