title: Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway.
abstract: Moscatilin is a bibenzyl derivative extracted from the Dendrobium aurantiacum var. denneanum, which has traditionally been used as an immunomodulatory treatment in China. The present study was designed to determine whether moscatilin is a pro‑apoptotic agent in pancreatic cancer, and to elucidate the underlying mechanisms. The apoptotic and anti‑proliferative effects of moscatilin on pancreatic cancer cells were determined in vitro using biochemical assays, such as the MTT assay, colony formation assay, Hoechst staining and DNA fragmentation assay, and in vivo using Panc‑1 pancreatic cancer xenografts. Western blotting was also conducted to evaluate the expression levels of B‑cell lymphoma 2 (Bcl2), Bcl2‑associated X protein (Bax), Bcl2 homologous antagonist killer (Bak), caspase 3, cleaved‑caspase 3, poly (ADP‑ribose) polymerase, p‑c‑Jun N‑terminal kinase (JNK)/stress‑activated protein kinases (SAPK) and JNK/SAPK in response to moscatilin. We used DCFH‑DA to detect the production of reactive oxygen species (ROS) induced by moscatilin. The present study demonstrated that moscatilin markedly inhibited pancreatic cancer cell viability and induced cell apoptosis in a concentration‑dependent manner. Conversely, moscatilin did not affect the cell viability of human umbilical vein endothelial cells at the comparable dosage. Treatment with moscatilin suppressed clonogenicity of Panc‑1 cells in a concentration‑dependent manner. Furthermore, a decrease in Bcl2 expression, and an increase in the expression levels of Bak and Bax, was detected following treatment with moscatilin, resulting in an increase in the proapoptotic/anti‑apoptotic expression ratio (Bax/Bcl2) in Panc‑1 cells. Moscatilin also induced activation of the caspase‑dependent mitochondrial apoptotic pathway. In addition, moscatilin enhanced cellular ROS production and induced activation of JNKSAPK signaling pathway. Conversely, pretreatment with the ROS scavenger N‑acetylcysteine or the JNK/SAPK‑specific inhibitor SP600125 prevented moscatilin‑mediated reductions in cell viability. Furthermore, moscatilin inhibited tumor growth in nude mice bearing Panc‑1 cells, without apparent toxicity. In conclusion, these results demonstrated that moscatilin may induce pancreatic cell apoptosis, and therefore may be considered a potential therapeutic agent for the treatment of pancreatic cancer.
authors.affiliation: Pancreatic Cancer Group, General Surgery Department, Zhongshan Hospital, Fudan University, Shanghai 200232, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Pancreatic Cancer Group, General Surgery Department, Zhongshan Hospital, Fudan University, Shanghai 200232, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Pancreatic Cancer Group, General Surgery Department, Zhongshan Hospital, Fudan University, Shanghai 200232, P.R. China.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Xu
authors.affiliation: Pancreatic Cancer Group, General Surgery Department, Zhongshan Hospital, Fudan University, Shanghai 200232, P.R. China.
authors.forename: Da-Yong
authors.initials: DY
authors.lastname: Jin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001593:Benzyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D001593:Benzyl Compounds; D017382:Reactive Oxygen Species; C071845:dendrophenol