Selenium-lentinan inhibits tumor progression by regulating epithelial-mesenchymal transition.

BACKGROUND: Selenium supplementation can be used to treat tumors. However, inorganic selenium is highly toxic, and natural organic selenium is extremely rare. Polysaccharides can improve drug bioavailability and targeting. Lentinan is a polysaccharide that has been approved as an anti-cancer drug in Japan and China. METHODS: Lentinan, an antitumor polysaccharide extracted from Lentinus edodes, was conjugated with seleninic acid to be transformed into ester (Se-lentinan) and utilized as drug carrier. The enhancement of the anti-tumor effects of Se-lentinan was evaluated by cell viability, cell cycle, migration, and transwell assays and animal xenograft models. The effects of Se-lentinan on the expression levels of epithelial-mesenchymal transition (EMT) markers were determined through immunofluorescence, Western blot, and immunohistochemistry analyses. RESULTS: Se-lentinan inhibited the invasiveness of B16-BL6 and HCT-8 cells by suppressing EMT. In vivo, Se-lentinan significantly inhibited tumor growth and metastasis of the transplanted melanoma and colon cancer cells and showed less toxicity than sodium selenite. Moreover, Se-lentinan reduced the accumulation of selenium in the liver and kidney tissues of mice and exhibited low organ toxicity. CONCLUSION: The antitumor activity of selenium was enhanced greatly, and its side effects were reduced with the use of lentinan as drug carrier.

Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters.

Multidrug resistance is a major problem in colon cancer treatment. However, its molecular mechanisms remain unclear. Recently, the epithelial-mesenchymal transition (EMT) in anticancer drug resistance has attracted increasing attention. This study investigated whether vincristine treatment induces EMT and promotes multidrug resistance in colon cancer. The result showed that vincristine treatment increases the expression of several ATP-binding cassette transporters in invasive human colon adenocarcinoma cell line (HCT-8). Vincristine-resistant HCT-8 cells (HCT-8/V) acquire a mesenchymal phenotype, and thus its migratory and invasive ability are increased both in vitro and in vivo. The master transcriptional factors of EMT, especially Twist1, were significantly increased in the HCT-8/V cell line. Moreover, the ectopic expression of Twist1 increased the chemoresistance of HCT-8 cells to vincristine and increased the expression levels and promoter activities of ABCB1 and ABCC1. Furthermore, Twist1 silencing reverses the EMT phenotype, enhances the chemosensitivity of HCT-8/ V cells to anticancer agents in vitro and in vivo, and downregulates the expression of ABCB1 and ABCC1. Twist1-mediated promotion of ABCB1 and ABCC1 expression levels plays an important role in the drug resistance of colon cancer cells.