cytochrome-c-t and Waldenstrom-Macroglobulinemia

cytochrome-c-t has been researched along with Waldenstrom-Macroglobulinemia* in 1 studies

Other Studies

1 other study(ies) available for cytochrome-c-t and Waldenstrom-Macroglobulinemia

Article	Year
XK469, a topo IIbeta inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways. International journal of oncology, 2003, Volume: 23, Issue:6 We have previously reported that XK469 inhibited topoisomerase (topo) IIbeta, in Waldenstrom's macroglobulinemia cell line (WSU-WM) however the inhibition alone is not sufficient to induce apoptosis. In this study, the apoptotic potential of XK469 and its mechanism in WSU-WM cell line was investigated. Exposure of WSU-WM cells to XK469 caused a decrease in viable cell number in a dose-dependent manner. In addition, XK469 caused the activation of caspase 3 resulting in subsequent cleavage of PARP. These events were preceded by the release of cytochrome c from the mitochondria to the cytosol. Simultaneous exposure of cells to cyclosporin A prevented the release of cytochrome c to cytosol and reduced the loss of viability. XK469 caused the activation of p53 with up-regulation of p53-dependent proteins such as Bax, p21, Gadd 45 and cyclin B1 in association with G2M arrest. The addition of ubiquitin carboxyl terminal hydrolase (UCH-L1) inhibitor (NaBH4) inhibited up-regulation of p53 and p53 related molecules by XK469 and reduced the loss of viability. Pre-incubation with NOK-1, a monoclonal antibody that prevents Fas-Fas ligand interaction and is inhibitory to Fas signaling interfered with XK469 induced activation of caspase 8 and also reduced the loss of viability. Simultaneous exposure of all three inhibitors (cyclosporin A, NaBH4 and NOK-1) abrogated the toxicity of XK469 by 95%. These data define multiple sequences of biochemical events that mediate cell death induced by XK469. Our study suggests a complex mechanistic cascade of XK469-mediated apoptosis that involves Fas signaling pathway, ubiquitination, p53 activation and cytochrome c release. Topics: Apoptosis; Blotting, Western; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Cycle; Cell Line, Tumor; Cell Survival; Cyclosporine; Cytochromes c; Cytosol; Densitometry; DNA Damage; DNA Topoisomerases, Type II; DNA-Binding Proteins; Dose-Response Relationship, Drug; Electron Transport Complex IV; Enzyme Activation; Enzyme Inhibitors; Fas Ligand Protein; Fluorometry; Humans; Ligands; Membrane Glycoproteins; Mitochondria; Models, Biological; Poly(ADP-ribose) Polymerases; Quinoxalines; Signal Transduction; Time Factors; Topoisomerase II Inhibitors; Tumor Suppressor Protein p53; Up-Regulation; Waldenstrom Macroglobulinemia	2003

Article

Year

XK469, a topo IIbeta inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways.

International journal of oncology, 2003, Volume: 23, Issue:6

We have previously reported that XK469 inhibited topoisomerase (topo) IIbeta, in Waldenstrom's macroglobulinemia cell line (WSU-WM) however the inhibition alone is not sufficient to induce apoptosis. In this study, the apoptotic potential of XK469 and its mechanism in WSU-WM cell line was investigated. Exposure of WSU-WM cells to XK469 caused a decrease in viable cell number in a dose-dependent manner. In addition, XK469 caused the activation of caspase 3 resulting in subsequent cleavage of PARP. These events were preceded by the release of cytochrome c from the mitochondria to the cytosol. Simultaneous exposure of cells to cyclosporin A prevented the release of cytochrome c to cytosol and reduced the loss of viability. XK469 caused the activation of p53 with up-regulation of p53-dependent proteins such as Bax, p21, Gadd 45 and cyclin B1 in association with G2M arrest. The addition of ubiquitin carboxyl terminal hydrolase (UCH-L1) inhibitor (NaBH4) inhibited up-regulation of p53 and p53 related molecules by XK469 and reduced the loss of viability. Pre-incubation with NOK-1, a monoclonal antibody that prevents Fas-Fas ligand interaction and is inhibitory to Fas signaling interfered with XK469 induced activation of caspase 8 and also reduced the loss of viability. Simultaneous exposure of all three inhibitors (cyclosporin A, NaBH4 and NOK-1) abrogated the toxicity of XK469 by 95%. These data define multiple sequences of biochemical events that mediate cell death induced by XK469. Our study suggests a complex mechanistic cascade of XK469-mediated apoptosis that involves Fas signaling pathway, ubiquitination, p53 activation and cytochrome c release.

Topics: Apoptosis; Blotting, Western; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Cycle; Cell Line, Tumor; Cell Survival; Cyclosporine; Cytochromes c; Cytosol; Densitometry; DNA Damage; DNA Topoisomerases, Type II; DNA-Binding Proteins; Dose-Response Relationship, Drug; Electron Transport Complex IV; Enzyme Activation; Enzyme Inhibitors; Fas Ligand Protein; Fluorometry; Humans; Ligands; Membrane Glycoproteins; Mitochondria; Models, Biological; Poly(ADP-ribose) Polymerases; Quinoxalines; Signal Transduction; Time Factors; Topoisomerase II Inhibitors; Tumor Suppressor Protein p53; Up-Regulation; Waldenstrom Macroglobulinemia

2003