Bis(acetylacetonato)-oxidovanadium(IV) and sodium metavanadate inhibit cell proliferation via ROS-induced sustained MAPK/ERK activation but with elevated AKT activity in human pancreatic cancer AsPC-1 cells.
In this study, the antiproliferative effect of bis(acetylacetonato)-oxidovanadium(IV) and sodium metavanadate and the underlying mechanisms were investigated in human pancreatic cancer cell line AsPC-1. The results showed that both exhibited an antiproliferative effect through inducing G2/M cell cycle arrest and can also cause elevation of reactive oxygen species (ROS) levels in cells. Moreover, the two vanadium compounds induced the activation of both PI3K/AKT and MAPK/ERK signaling pathways dose- and time-dependently, which could be counteracted with the antioxidant N-acetylcysteine. In the presence of MEK-1 inhibitor, the degradation of Cdc25C, inactivation of Cdc2 and accumulation of p21 were relieved. However, the treatment of AKT inhibitor did not cause any significant effect. Therefore, it demonstrated that the ROS-induced sustained MAPK/ERK activation rather than AKT contributed to vanadium compounds-induced G2/M cell cycle arrest. The current results also exhibited that the two vanadium compounds did not induce a sustained increase of ROS generation, but the level of ROS reached a plateau instead. The results revealed that an intracellular feedback loop may be against the elevated ROS level induced by vanadate or VO(acac)2, evidenced by the increased GSH content, the unchanged level at the expression of antioxidant enzymes. Therefore, vanadium compounds can be regarded as a novel type of anticancer drugs through the prolonged activation of MAPK/ERK pathway but retained AKT activity. The present results provided a proof-of-concept evidence that vanadium-based compounds may have the potential as both antidiabetic and antipancreatic cancer agents to prevent or treat patients suffering from both diseases.
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People's Republic of China.
Jing-Xuan
JX
Wu
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People's Republic of China.
Yi-Hua
YH
Hong
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People's Republic of China. yxg@bjmu.edu.cn.
Xiao-Gai
XG
Yang
D000111:Acetylcysteine / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D014638:Vanadates / Q000494:pharmacology*
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D014638:Vanadates; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione; D000111:Acetylcysteine
AsPC-1 cells; Extracellular signal-regulated protein kinase; PI3K/AKT signaling pathway; Reactive oxygen species; Vanadium compounds