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

Abstract

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.

• Authors: Edith Mensah-Osman, Ayad Al-Katib, Mahmoud Dandashi, Ramzi Mohammad
• Journal: International journal of oncology (Int J Oncol) Vol. 23 Issue 6 Pg. 1637-44 (Dec 2003) ISSN: 1019-6439 [Print] Greece
• PMID: 14612935 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• Enzyme Inhibitors
• FASLG protein, human
• Fas Ligand Protein
• Ligands
• Membrane Glycoproteins
• Quinoxalines
• Topoisomerase II Inhibitors
• Tumor Suppressor Protein p53
• XK 469
• Cyclosporine
• Cytochromes c
• Electron Transport Complex IV
• Poly(ADP-ribose) Polymerases
• CASP3 protein, human
• CASP8 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 8
• Caspase 9
• Caspases
• DNA Topoisomerases, Type II

Topics

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