The colchicine derivative CT20126 shows a novel microtubule-modulating activity with apoptosis

New colchicine analogs have been synthesized with the aim of developing stronger potential anticancer activities. Among the analogs, CT20126 has been previously reported to show immunosuppressive activities. Here, we report that CT20126 also shows potential anticancer effects via an unusual mechanism: the modulation of microtubule integrity and cell cycle arrest at the G2/M phase before apoptosis. When we treated COS-7 cells with CT20126 (5 μM), the normal thread-like microtubules were disrupted into tubulin dimers within 10 min and thereafter repolymerized into short, thick filaments. In contrast, cells treated with the same concentration of colchicine exhibited microtubule depolymerization after 20 min and never underwent repolymerization. Furthermore, optical density (OD) analysis (350 nm) with purified tubulin showed that CT20126 had a higher repolymerizing activity than that of Taxol, a potent microtubule-polymerizing agent. These results suggest that the effects of CT20126 on microtubule integrity differ from those of colchicine: the analog first destabilizes microtubules and then stabilizes the disrupted tubulins into short, thick polymers. Furthermore, CT20126 induced a greater level of apoptotic activity in Jurkat T cells than colchicine (assessed by G2/M arrest, caspase-3 activation and cell sorting). At 20 nM, CT20126 induced 47% apoptosis among Jurkat T cells, whereas colchicine induced only 33% apoptosis. Our results suggest that the colchicine analog CT20126 can potently induce apoptosis by disrupting microtubule integrity in a manner that differs from that of colchicine or Taxol. Colchicine's value as an anticancer drug is undercut by harmful side effects, but a related compound may offer a useful alternative. Cell division is facilitated by dynamic assembly and disassembly of tubulin protein into microtubule filaments, which ensure that each new cell receives a full set of chromosomes. Colchicine thwarts cancerous growth by forcing microtubule disassembly. Since it can also be toxic to patients, Jong-Soo Chang of Korea's Daejin University and colleagues characterized the anticancer effects of a colchicine derivative called CT20126. Unlike colchicine, CT20126 only transiently stimulates microtubule disassembly, and subsequently promotes aggregation of tubulin into unusually short, thick filaments. Nevertheless, CT20126 still proved a potent inhibitor of proliferation in cultured human cells, and triggered programmed cell death more efficiently than other microtubule-targeting drugs, highlighting its potential as a therapeutic candidate.