title: Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species.
abstract: The prognosis of gastric cancer remains poor due to clinical drug resistance. Novel drugs are urgently needed. Shikonin (SHK), a natural naphthoquinone, has been reported to trigger cell death and overcome drug resistance in anti-tumour therapy. In this study, we investigated the effectiveness and molecular mechanisms of SHK in treatment with gastric cancer. In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells. SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis. We confirmed that SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade, but also in a caspase-independent manner which mediates the nuclear translocation of apoptosis-inducing factor and Endonuclease G. Furthermore, we demonstrated that SHK enhanced the chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin in vitro and in vivo. Taken together, our data show that SHK may be a novel therapeutic agent in the clinical treatment of gastric cancer.
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P. R. China.
authors.forename: Wenquan
authors.initials: W
authors.lastname: Liang
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P. R. China.
authors.forename: Aizhen
authors.initials: A
authors.lastname: Cai
authors.affiliation: Department of Frontier for Biological Treatment, Beijing Institute of Basic Medical Science, Beijing, 100850, China.
authors.forename: Guozhu
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P. R. China.
authors.forename: Hongqing
authors.initials: H
authors.lastname: Xi
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P. R. China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P. R. China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P. R. China.
authors.forename: Kecheng
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P. R. China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Frontier for Biological Treatment, Beijing Institute of Basic Medical Science, Beijing, 100850, China.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P. R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.affiliation: Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing 100853, P. R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009285:Naphthoquinones / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: D009285:Naphthoquinones; D009944:Organoplatinum Compounds; D011725:Pyridines; D017382:Reactive Oxygen Species; C431073:oxiplatin; C016101:shikonin; D005472:Fluorouracil