Abstract. Wogonin (5,7-dihydroxy-8-methoxyflavone) is a flavone constituent of Scutellaria baicalensis with various beneficial biological activities and it has been shown to have tumor therapeutic potential in vitro and in vivo. The purpose of this study was to investigate the effects of wogonin in a human osteosarcoma cell line (U-2 OS). Results showed that a dose-and time-dependent reduction occurred in cell viability after exposure to wogonin in U-2 OS cells. Increasing the levels of reactive oxygen species (ROS) and Ca 2+ but decreasing the levels of mitochondrial membrane potential (∆Ψm) were examined in wogonin-treated U-2 OS cells. Flow cytometric assay indicated that wogonin induced sub-G1 phase (apoptosis) and increased caspase-3 activity in examined cells. Wogonin-induced apoptosis in U-2 OS cells was also confirmed by 4' ,6-diamidino-2-phenylindole (DAPI) staining. Also, results from Western blotting indicated that wogonin increased the levels of Bad, Bax, cytochrome c, cleaved caspase-9, cleaved caspase-3, AIF, Endo G, Fas/CD95, caspase-8, GADD153, GRP78, ATF-6α, calpain 1, calpain 2 and caspase-4 then leading to cell apoptosis. In conclusion, wogonin induced ROS production and intracellular Ca 2+ , and altered the levels of anti-(Bcl-2) and pro-(Bad and Bax) apoptotic proteins. Wogonin-induced apoptosis in U-2 OS cells was through the activation of caspase-3. In conclusion, these are the first findings to show wogonin-induced cytotoxic effects through induction of apoptotic cell death and ER stress in U-2 OS cells. The potent in vitro antitumor activities suggest that wogonin could be developed for the treatment of human osteosarcoma in the future.
Abstract. We investigated the microsatellite alterations in mitochondrial DNA (mtDNA) and in TP53 in thoracic esophageal squamous cell carcinomas (TESCC). Using laser microdissection, 66 paired non-cancerous esophageal muscles, non-cancerous esophageal mucosa, cancerous TESCC nests plus 35 metastatic lymph nodes harvested from 66 resected esophagi of TESCC patients were subjected to DNA extraction. D310 and D17S960 were chosen as markers to address microsatellite alterations in mtDNA, including changes in copy number and homoplasmic/heteroplasmic mutations of mtDNA, and in TP53, including loss of heterozygosity (LOH) and microsatellite instability (MI). From non-cancerous esophageal mucosa to cancerous TESCC nests and then metastatic lymph nodes, a trend of homoplasmic D310 mutation (10.6, 25.8, 31.4%; P=0.023), an ever increase of mtDNA copy ratios (0.892, 1.128, 1.183; P=0.018) and an elevated incidence of TP53 LOH (19.7, 34.8,37.1%; P=0.010) were observed. From T1, T2, T3 to T4 TESCC, the incidence of TP53 LOH (12.5, 16.7, 34.8, 52.2%; P=0.011) was increased, in a stepwise fashion. Furthermore, we observed an association of TP53 LOH with an increased mtDNA copy ratio (P=0.022) and TP53 MI with heteroplasmic D310 mutation (P=0.069) in TESCC. Concurrent and associated microsatellite alterations in mtDNA and in TP53 in TESCC support the cancer clonal expansion theory and imply a possible relationship between the mitochondria and p53 in TESCC.
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