title: Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells.
abstract: Cambogin is a polycyclic polyprenylated acylphoroglucinol (PPAP) from the Garcinia genus, which has been used traditionally for cancer treatment across Southeastern Asia. In this study, we found that cambogin inhibited breast cancer cell proliferation and induced cell apoptosis in vitro. Cambogin induced the activation of the caspase-independent mitochondrial apoptotic pathway, as indicated by an increase in the ratio of Bax/Bcl-2 and the nuclear translocation of apoptosis inducing factor (AIF). Two-dimensional gel electrophoresis and mass spectrometry revealed that the expression of proteins involving in the radical oxygen species (ROS) pathway was among the most affected upon cambogin treatment. Cambogin enhanced cellular ROS production, and induced the activation of the ASK1-MKK4/MKK7-JNK/SAPK signaling pathway. Pretreatment with ROS scavenger N-acetylcysteine (NAC), an antioxidant, or the JNK inhibitor SP600125 was able to restore cell viability in the presence of cambogin. Importantly, cambogin treatment led to the activation of activating transcription factor-2 (ATF-2) and the trimethylation of histone H3K9 in the activator protein 1 (AP-1) binding region of the Bcl-2 gene promoter. Finally, cambogin exhibited a potential antitumor effect in MCF-7 breast cancer xenografts without apparent toxicity. Taken in conjunction, the present study indicates that cambogin can induce breast adenocarcinoma cell apoptosis and therefore represents therapeutic potential for cancer treatment.
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Kaikai
authors.initials: K
authors.lastname: Shen
authors.affiliation: South Australian Health & Medical Research Institute, North Terrace, Adelaide, Australia. Centre for Biological Sciences, Life Science Building, University of Southampton, Southampton, United Kingdom.
authors.forename: Jianling
authors.initials: J
authors.lastname: Xie
authors.affiliation: Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Yu
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lu
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Tan
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China. xuhongxi88@gmail.com.
authors.forename: Hongxi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015180:Electrophoresis, Gel, Two-Dimensional; D044127:Epigenesis, Genetic; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D040901:Proteomics / Q000379:methods; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013729:Terpenes; D020169:Caspases; C054597:garcinol; D000111:Acetylcysteine