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.
Highlights
SHK induces apoptosis in the human gastric cancer cells HGC-27 through mitochondria-mediated pathway[20] and causes cell cycle arrest in human gastric cancer (AGS) by early growth response 1 (Egr1)-mediated p21 gene expression[21]
The results showed that SHK induces the generation of intracellular Reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP), releases Cytochrome C from mitochondria and induces apoptosis via the caspase cascade
SHK is a naphthoquinone extracted from Chinese herbal medicine plant and is considered to be safe due to its long history use in Chinese traditional medicine
Summary
SHK induces apoptosis in the human gastric cancer cells HGC-27 through mitochondria-mediated pathway[20] and causes cell cycle arrest in human gastric cancer (AGS) by early growth response 1 (Egr1)-mediated p21 gene expression[21]. Researchers discovered that cells can die and display apoptosis morphology without caspase activation via the translocation of apoptosis inducing factor (AIF) and Endonuclease G (Endo G) from the mitochondria to nucleus[30,31]. This sheds new light on overcoming the drug resistance for the tumours which are not sensitive to caspase dependent apoptosis. The results showed that SHK induces the generation of intracellular ROS, depolarizes the mitochondrial membrane potential (MMP), releases Cytochrome C from mitochondria and induces apoptosis via the caspase cascade. These results indicate that SHK is a novel inducer of apoptosis in gastric cancer and a promising candidate as a chemo-sensitizer for drug resistant gastric cancer patients
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