Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species

• Published in: Scientific reports Vol. 6; no. 1; p. 38267
• Main Authors: Liang, Wenquan, Cai, Aizhen, Chen, Guozhu, Xi, Hongqing, Wu, Xiaosong, Cui, Jianxin, Zhang, Kecheng, Zhao, Xudong, Yu, Jiyun, Wei, Bo, Chen, Lin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2016; Nature Publishing Group
• Subjects: 13/109; 13/2; 13/31; 13/89; 14/1; 14/19; 14/63; 42/44; 42/89; 5-Fluorouracil; 631/67/1504/1829; 631/80/82/23; 64/60; Apoptosis; Apoptosis - drug effects; Apoptosis-inducing factor; Caspase; Cell death; Cell Line, Tumor; Cell proliferation; Cytochrome c; Drug resistance; Endonuclease; Epithelial cells; Fluorouracil - pharmacology; Gastric cancer; Humanities and Social Sciences; Humans; Membrane potential; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Molecular modelling; multidisciplinary; Naphthoquinones - pharmacology; Nuclear transport; Organoplatinum Compounds - pharmacology; Oxaliplatin; Pyridines - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Shikonin; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Translocation; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep38267

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.