Sanguinarine (SAG), a benzophenanthridine
alkaloid extracted from Sanguinaria canadensis, exerts
antioxidant, anti-inflammatory and antiproliferative activities in a variety of
malignancies. However, the underlying mechanisms by which SAG affects the
tumorigenesis of
gastric cancer (GC) are unclear. The common targets of SAG and GC were identified by network pharmacology, and the association of thymocyte selection-associated high mobility group box (TOX) with the clinicopathological characteristics and prognosis of patients with GC was analyzed by using datasets from The
Cancer Genome Atlas (TCGA). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium
bromide (MTT) assays, colony formation assays, flow cytometry analysis, and a xenograft
tumor model were conducted to assess the effects of SAG on the growth of GC cells, and Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were used to determine the effects of SAG on the TOX/
DNA-
PKcs/KU70/80 signaling pathway. We identified 9 collective targets of SAG and GC, of which TOX expression levels were dramatically downregulated in GC tissues compared with adjacent normal tissues, and a low expression of TOX served as an independent prognostic factor of poor survival in patients with GC. SAG suppressed cell viability, colony formation and in vivo
tumorigenesis and induced cell apoptosis and cell cycle arrest. Furthermore, SAG increased the expression levels of TOX but decreased those of
DNA-
PKcs and KU70/80 in GC cells. Our findings indicate that SAG inhibits the
tumorigenesis of GC cells by regulating TOX/
DNA-
PKcs/KU70/80 signaling and may provide therapeutic strategies for the treatment of GC.