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Cytotoxic effect through fas/APO-1 expression due to vitamin K in human glioma cells
1Department of Neurosurgery, University of the Ryukyus, Faculty of Medicine, Okinawa, Japan.
Abstract:
Congeners of vitamin K have been found to inhibit growth in various rodent and human tumor cells, but the mechanisms of the inhibitory action are still not well understood. To investigate the modes of actions of vitamin K, we used several vitamin K analogs and examined their cytotoxic effect for human glioma cell lines RBR17T and U251. The analogs included vitamin K1 (VK1), vitamin K2 (VK2), vitamin K3 (VK3), and geranylgeraniol (GGO) which form an unsaturated side chain of VK2. Cell viability was estimated by MTT assay. DNA fragmentation was demonstrated by gel electrophoresis and flow cytometry. In order to study the mechanism of apoptosis, we measured the changes of intracellular reactive oxygen intermediates (ROI) and Fas/APO-1 expression by flow cytometry. The results showed: (1) VK2, VK3, and GGO inhibited cell growth; (2) VK3 had a more potent cytotoxic effect than VK2, and VK3 enhanced the cytotoxic effect of antitumor agents (ACNU and IFN-beta) in RBR17T cells; (3) VK2, VK3, and GGO induce apoptosis: (4) VK3 increased the expression of Fas/APO-1 although VK2 and GGO did not increase its expression in glioma cells; (5) VK3 increased the production of intracellular ROI. Catalase and reduced glutathione (GSH) inhibited production of intracellular ROI and antagonized inhibition of cell-growth induced by VK3, but failed to antagonize that of VK2 and GGO. We hypothesize that VK3 induces apoptosis by promoting the generation of intracellular ROI and Fas/APO-1 expression. On the other hand, VK2 and GGO induce apoptosis but most likely by some other unknown pathway.
Insights
Vitamin K3 (VK3) and other analogs inhibit glioma cell growth by inducing apoptosis. VK3 promotes cell death via reactive oxygen intermediates and Fas/APO-1 expression, unlike VK2 and geranylgeraniol.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Vitamin K congeners exhibit anti-tumor properties in various cell types.
- The precise mechanisms underlying vitamin K's inhibitory effects on tumor growth remain largely unelucidated.
Purpose of the Study:
- To investigate the cytotoxic effects and apoptotic mechanisms of vitamin K analogs on human glioma cell lines.
- To elucidate the roles of intracellular reactive oxygen intermediates (ROI) and Fas/APO-1 expression in vitamin K-induced apoptosis.
Main Methods:
- Utilized human glioma cell lines (RBR17T and U251) treated with vitamin K analogs (VK1, VK2, VK3) and geranylgeraniol (GGO).
- Assessed cell viability using MTT assay, DNA fragmentation via gel electrophoresis and flow cytometry.
- Quantified intracellular ROI and Fas/APO-1 expression using flow cytometry.
Main Results:
- Vitamin K2 (VK2), VK3, and GGO demonstrated significant inhibition of glioma cell growth.
- VK3 exhibited a more potent cytotoxic effect than VK2 and enhanced the efficacy of conventional antitumor agents (ACNU, IFN-beta).
- VK2, VK3, and GGO induced apoptosis; VK3 uniquely upregulated Fas/APO-1 expression and increased intracellular ROI production, which was counteracted by catalase and GSH.
Conclusions:
- Vitamin K3 (VK3) induces apoptosis in glioma cells through increased intracellular ROI and Fas/APO-1 expression.
- Vitamin K2 (VK2) and geranylgeraniol (GGO) also induce apoptosis, but likely via distinct, currently unknown pathways.
