Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of DNA topoisomerase (Topo) IIbeta in cancer chemotherapy remains unclear, although this particular isoform has been implicated in drug resistance. In this study, we investigated Topo IIbeta as a target for 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469), a novel synthetic quinoxaline phenoxypropionic acid derivative, in a Waldenstrom's macroglobulinemia (WM) model. In vitro, the WSU-WM cell line was exposed to 1.0, 2.0, 5.0, 8.0, and 10 microM XK469. Our results demonstrate a concentration-dependent cell growth inhibition with a concentration-independent inhibition of Topo IIbeta, as determined by band depletion assay. The cell growth inhibition of cells correlated well with increase in Bax:Bcl-2 ratio and poly(ADP-ribose) polymerase (PARP) cleavage. We used our established WSU-WM severe combined immunodeficient mouse xenograft model to test the efficacy and effect of XK469 on Topo IIbeta in vivo. Topo IIbeta was inhibited equally using two different dose schedules (20 and 40 mg/kg, i.v., for a total of 120 and 240 mg/kg, respectively); however, there was no significant decrease in tumor weight. Western blot analysis of cells isolated from s.c. tumors showed no induction of the Bax protein and a very low Bax:Bcl-2 ratio of approximately 0.3 in correlation with minimum PARP cleavage. Our study shows that XK469 inhibits Topo IIbeta in WSU-WM cells both in vitro and in vivo at or below the maximum tolerated dose in severe combined immunodeficient mice. However, there was no change of apoptosis-related molecules such as PARP, Bax, and Bcl-2 or reduction in tumor weight in association with Topo IIbeta inhibition. We conclude that Topo IIbeta inhibition by XK469 as a target is not sufficient for therapeutic effects in WSU-WM.
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PMID:2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469) inhibition of topoisomerase IIbeta is not sufficient for therapeutic response in human Waldenstrom's macroglobulinemia xenograft model. 1251 64

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.
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PMID:XK469, a topo IIbeta inhibitor, induces apoptosis in Waldenstrom's macroglobulinemia through multiple pathways. 1461 35