A new bis-indole, KARs, induces selective M arrest with specific spindle aberration in neuroblastoma cell line SH-SY5Y

KARs, new semisynthetic antitumor bis-indole derivatives, were found to be inhibitors of tubulin polymerization with lower toxicity than vinblastine o r vincristine, used in chemotherapy. Here, we compare the effect of KARs wi th those of vinblastine and vincristine on cell viability, cell proliferati on, and cell cycle in neuroblastoma cell line (SH-SY5Y). At concentrations of the different compounds equivalent in causing 50% of inhibition of cell growth, KARs induced a complete arrest in the G(2)/M phase, whereas vinblas tine and vincristine induced a partial arrest in both G(O)/G(1) and G(2)/M. Moreover, a combination of KAR-2 and W13 (an anticalmodulin drug) qualitat ively caused similar arrest in both G(O)/G(1) and G(2)/M than vinblastine. Levels of cyclin A and B1 were higher in KARs-treated cells than in vinblas tine- or vincristine-treated cells. Cdc2 activity was much higher in KAR-2 than in vinblastine-treated cells, indicating a stronger mitotic arrest. Th e effect of KAR2 and vinblastine on microtubules network was analyzed by im munostaining with anti-tubulin antibody. Results indicated that KAR-2-induc es the formation of aberrant mitotic spindles, with not apparent effect on interphase microtubules, whereas vinblastine partially destroyed interphase microtubules coexisting with normal and aberrant mitotic spindles.