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

  • Authors:
    • Edith Mensah-Osman
    • Ayad Al-Katib
    • Mahmoud Dandashi
    • Ramzi Mohammad
  • Corresponding author:
  • View Affiliations

  • Published online on: Monday, December 1, 2003
  • Pages: 1637-1644 DOI: 10.3892/ijo.23.6.1637

Abstract

We have previously reported that XK469 inhibited topoisomerase (topo) IIβ, 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.
Journal Cover

December 2003
Volume 23 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

2014 Impact Factor: 3.025
Ranked #30/211 Oncology
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APA
Mensah-Osman, E., Al-Katib, A., Dandashi, M., & Mohammad, R. (2003). XK469, a topo IIβ inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways. International Journal of Oncology, 23, 1637-1644. http://dx.doi.org/10.3892/ijo.23.6.1637
MLA
Mensah-Osman, E., Al-Katib, A., Dandashi, M., Mohammad, R."XK469, a topo IIβ inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways". International Journal of Oncology 23.6 (2003): 1637-1644.
Chicago
Mensah-Osman, E., Al-Katib, A., Dandashi, M., Mohammad, R."XK469, a topo IIβ inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways". International Journal of Oncology 23, no. 6 (2003): 1637-1644. http://dx.doi.org/10.3892/ijo.23.6.1637