Identification of a new cyathane diterpene that induces mitochondrial and autophagy-dependent apoptosis and shows a potent in vivo anti-colorectal cancer activity

• DOI: 10.1016/j.ejmech.2016.01.056
• Publication Date: 2016-02-01T10:30:34Z
• Authors: Luwei He; Junjie Han; Baowei Li; Li Huang; Ke Ma; Quan Chen; Xinzhong Liu; Li Bao; Hongwei Liu
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Dose-Response Relationship, Drug; Molecular Structure; Cell Survival; Mice, Nude; Antineoplastic Agents; Apoptosis; Neoplasms, Experimental; HCT116 Cells; Mitochondria; 3. Good health; Mice; Structure-Activity Relationship; 03 medical and health sciences; Autophagy; Tumor Cells, Cultured; Animals; Humans; Diterpenes; Drug Screening Assays, Antitumor; Colorectal Neoplasms; Cell Proliferation

Diterpenes has been reported to possess multiple bioactivities consisting of anti-microbial and anti-inflammatory properties. This study reveals a new cyathane-type diterpene (cyathin Q) from the culture of the fungus Cyathus africanus by bioactivity-guided separation. The structure of cyathin Q was determined based on spectroscopic measurements (NMR and MS). The bioactivity evaluation shows that cyathin Q has a strong anticancer activity against HCT116 cells and Bax-deficient HCT116 in vitro and in vivo. This compound induced hallmarks of apoptotic events in HCT116 cells, including caspase activation, cytochrome c release, poly (ADP-ribose) polymerase (PARP) cleavage, and depolarization of the mitochondrial inner transmembrane potential. This process is accompanied with the increased mitochondrial ROS, down-regulation of Bcl-2 protein, and up-regulation of Bim protein. We also observed the cleavage of autophagy-related protein ATG5 in cyathin Q-induced apoptosis. Taken together, our study identified a new fungal diterpene that exhibited anticancer activity via induction of mitochondria and autophagy-dependent apoptosis in HCT116 cells.