Mycoepoxydiene, a fungal polyketide inhibits MCF-7 cells through simultaneously targeting p53 and NF-κB pathways

Mycoepoxydiene (MED) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp. HLY-1, which is associated with mangroves: however, the mechanism of action of MED remains unknown. Here, we report the molecular mechanisms of apoptosis activation and growth inhibition induced by MED in MCF-7 cells. The present results show that MED induces DNA damage through the production of reactive oxygen species (ROS), which resulted in the phosphorylation of H2AX and the activation of the Ataxia telangiectasia mutated kinase (ATM) and p53 signaling pathways. In addition, MED increases the accumulation of I kappa B alpha and enhances the association between IKK gamma and Hsp27 via the activation of Hsp27, which eventually resulted in the inhibition of TNF-alpha-induced NF-kappa B transactivation. Therefore, we conclude that MED inhibits MCF-7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF-kappa B to disrupt cell proliferation. Because small molecules having both of these effects are rare, further exploration of MED as an antitumor lead compound is needed. (C) 2012 Elsevier Inc. All rights reserved.