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  • 1
    Publication Date: 2018-01-04
    Description: Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L ., has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma. Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro . The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array. Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3β. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3β inactivation. Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3β inactivation–mediated repression of the Hedgehog/Gli1 pathway. Clin Cancer Res; 24(1); 130–44. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2018-06-02
    Description: We here evaluated the antiesophageal cancer cell activity by the antifungal drug itraconazole. Our results show that μg/mL concentrations of itraconazole potently inhibited survival and proliferation of established (TE-1 and Eca-109) and primary human esophageal cancer cells. Itraconazole activated AMPK signaling, which was required for subsequent esophageal cancer cell death. Pharmacologic AMPK inhibition, AMPKα1 shRNA, or dominant negative mutation (T172A) almost completely abolished itraconazole-induced cytotoxicity against esophageal cancer cells. Significantly, itraconazole induced AMPK-dependent autophagic cell death (but not apoptosis) in esophageal cancer cells. Furthermore, AMPK activation by itraconazole induced multiple receptor tyrosine kinases (RTKs: EGFR, PDGFRα, and PDGFRβ), lysosomal translocation, and degradation to inhibit downstream Akt activation. In vivo , itraconazole oral gavage potently inhibited Eca-109 tumor growth in SCID mice. It was yet ineffective against AMPKα1 shRNA-expressing Eca-109 tumors. The in vivo growth of the primary human esophageal cancer cells was also significantly inhibited by itraconazole administration. AMPK activation, RTK degradation, and Akt inhibition were observed in itraconazole-treated tumors. Together, itraconazole inhibits esophageal cancer cell growth via activating AMPK signaling. Mol Cancer Ther; 17(6); 1229–39. ©2018 AACR .
    Print ISSN: 1535-7163
    Electronic ISSN: 1538-8514
    Topics: Medicine
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