A novel compound that disrupts mitotic spindle poles in human cells

Abstract

We characterize the mechanism of action of a new microtubule-targeting compound in cells. Microtubule-targeting drugs are used as successful anti-cancer therapies. We synthesized a family of compounds that share a common scaffold and have several functional groups amenable to modifications. We found that one of the active derivatives, C75, reduces cell viability and prevents microtubule polymerization in vitro. In this study, we explore the phenotypes caused by C75 in cells. It causes mitotic arrest and spindle phenotypes in several cancer cell lines in the nanomolar range. C75 can bind to the Colchicine-pocket on tubulin in vitro, but causes different effects on microtubules in cells. While Colchicine causes a decrease in microtubules and spindle pole collapse without re-growth, similar concentrations of C75 cause a rapid loss of microtubules and spindle pole fragmentation followed by microtubule re-growth to form multipolar spindles. In addition, C75 and Colchicine synergize for reduced viability and spindle phenotypes. Importantly, the phenotypes caused by C75 are similar to those caused by the depletion of ch-TOG, a microtubule polymerase, and tubulin and ch-TOG are displaced and oscillate in C75-treated cells. This suggests that C75 causes microtubule depolymerization in cells either directly or indirectly via inhibiting ch-TOG. This unique effect of C75 on microtubules warrants further exploration of its anti-cancer potential.

Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones

“…Multipolar and “bipolar misaligned” spindles were described by Jaunky et al in cells treated with colchicine and C75 (new CBSIs), depending on concentration and (in the case of C75) cell line used. The authors supposed that the discrepancy in mitotic phenotypes caused by C75 between different cell lines might be connected with genetically-dependent sensitivity to spindle disruption [ 36 ]. However, observed aberrations are not only specific for tubulin inhibitors but also other compounds targeting mitotic spindle.…”