Mitotic arrest induced by XK469, a novel antitumor agent, is correlated with the inhibition of cyclin B1 ubiquitination

✍ Scribed by Hong Lin; Xiang Y. Liu; Balanehru Subramanian; Alexander Nakeff; Fred Valeriote; Ben D. Chen

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: French
• Weight: 247 KB
• Volume: 97
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.1570

✦ Synopsis

Abstract

XK469 (NSC 697887) is a novel antitumor agent with broad activity against a variety of tumors. Previous studies suggest that XK469 is a topoisomerase IIβ poison with functional activity similar to that of 4′‐(9‐acridinylamino) methanesulfon‐m‐anisidide (m‐AMSA). The goal of our study was to investigate its mechanism of action further using a human HCT‐116 (H116) colon tumor cell model. Concentration‐survival curves with continuous exposure indicated that XK469 had low cytotoxic activity against H116 cells. Cell cycle analysis revealed that XK469 is a phase‐specific cell cycle blocker that is associated with increased levels of cyclin B1, cyclin A and p53 but not CDK1 (cdc2) or cyclin E. In contrast, treatment of H116 cells with m‐AMSA caused a total degradation of both cyclin A and B1 but enhanced expression of cyclin E and p53. Accumulation of cyclin B1 in XK469‐treated cells was correlated with the inhibition of cyclin B1 ubiquitination, a metabolic process mandatory for proteasome‐mediated protein turnover. However, no inhibition of cyclin B1 ubiquitination was detected in cells treated with m‐AMSA or colchicine, a known mitotic inhibitor. Furthermore, unlike m‐AMSA, XK469 did not induce caspase activation or apoptotic cell death in H116 cells. Our results suggest that XK469 is a phase‐specific cell cycle inhibitor with a unique mechanism of action that is correlated with the inhibition of cyclin B1 ubiquitination and its accumulation at early M phase. © 2002 Wiley‐Liss, Inc.