Contrasting effects of microtubule destabilizers versus stabilizers on induction of death in G1 phase of the cell cycle.

Microtubule targeting agents (MTAs) have been reported to manifest their cytotoxic effects not only in mitosis but also in interphase. However, the relationship between phase-specific susceptibility and MTA concentration, especially with respect to microtubule integrity, remains poorly defined. In addition, whether microtubule stabilizers and destabilizers act similarly or differ in the ability to induce interphase death is unclear. In order to resolve these uncertainties, we report here the results of a systematic comparison of primary acute lymphoblastic leukemia (ALL) and HeLa cells treated with three different MTAs, namely the microtubule stabilizer paclitaxel and two microtubule destabilizers, vincristine, and eribulin. Both types of cells were sensitive to each MTA, with IC50 values in the sub-nanomolar to low nanomolar range. Primary ALL cells arrested in mitosis when treated with paclitaxel at all tested concentrations, whereas the effects of vincristine or eribulin were concentration-dependent; low (< 30 nM) concentrations induced mitotic death whereas higher concentrations (>100 nM) induced death directly in G1 phase. G1 phase death in response to higher concentrations of the destabilizers was associated with complete loss of interphase microtubule structure. In contrast, HeLa cells were only susceptible in M phase regardless of drug type or concentration. These results represent an important advance in our understanding and appreciation of microtubule function, and indicate that susceptibility to MTAs in G1 phase is both cell type- and drug type-restricted. The findings have important implications for the clinical use of MTAs especially in the context of drug combinations.