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Mycoepoxydiene (MED) is a polyketide isolated from a marine fungi associated with mangrove forests.This study found MED was cytotoxic to MCF-7 cells with an IC50 of 14 μM.MED inhibited the growth of MCF-7 cells by the induction of apoptosis partly via caspases at a dose-and time-dependent manner.On another hand,MED induced DNA double-strand (ds) breaks in MCF-7 cells,and led to H2AX phosphorylation (denoted γ-H2AX) in time-and concentration-dependent manners,then activated ATM-H2AX/Chk2-p53 signaling pathway.Indeed,MED induced apoptosis through the generation of reactive oxygen species (ROS) in MCF-7 cells: pretreatment with N-acetyl-L-cysteine (NAC) scavenged MED-induced ROS,and prevented cell death,suggesting that MED-induced apoptosis is attributed to its induction of ROS.MED induces MCF-7 cell apoptosis by activating p53 probably through responding to ds breaks in chromosomal DNA,assumably caused by MED-induced ROS,by the identity has yet to be revealed dsDNA break-sensor to transfer signals to the ATM kinase.ATM,in turn,transfers its signals on to the ATR (ATM-related) kinase,which is able to phosphorylate p53 itself;ATM also appears able to directly phosphorylate p53.This phosphorylation of p53 protects it from destruction.In parallel,MED increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27,which together eventually resulted in the inhibition of TNF-α-induced NF-κB transactivation.These results demonstrate that MED,a structurally novel natural product,with an unusual effect on cellular signaling induced apoptosis.This work provided the first report of a mechanistic framework that explains the in vitro inhibition of tumor cells by MED,which deserves further exploration of MED for use as an antitumor lead compound.