Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules.

摘要: // Erica Di Cesare 1 , Annalisa Verrico Andrea Miele 1, 2 Maria Giubettini 3 Paola Rovella Antonio Coluccia 4 Valeria Famiglini Giuseppe La Regina Enrico Cundari Romano Silvestri Patrizia Lavia Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department Biotechnology, Sapienza Universita di Roma, Italy Present address: IRBM Science Park, Advent Srl, Pomezia, EMBL, Heidelberg, Germany Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Drug Chemistry Technology, Correspondence to: Lavia, email: patrizia.lavia@uniroma1.it Keywords: mitotic spindle microtubules, tubulin inhibitors, cell death, caspase-3, time-lapse imaging Received: April 13, 2016      Accepted: January 06, 2017      Published: February 01, 2017 ABSTRACT Tubulin-targeting molecules are widely used cancer therapeutic agents. They inhibit microtubule-based structures, including the spindle, ultimately preventing division. The final fates microtubule-inhibited cells however often heterogeneous difficult to predict. While recent work has provided insight into response inhibitors microtubule dynamics (taxanes), polymerization remains less well characterized. Arylthioindoles (ATIs) recently developed inhibitors. We previously identified ATI members that effectively in vitro growth bulk viability assays. Here we characterise depth lines five selected ATIs. find all ATIs arrest progression, yet subsequently yield distinct fate profiles recording assays, indicating endowed with similar inhibitory activity can fact display differential efficacy living cells. Individual induce cytological phenotypes increasing severity terms damage apparatus. That differentially triggers MCL-1 down-regulation caspase-3 activation, underlies terminal treated Collectively, these results contribute define pinpoint potentially valuable increase molecular diversity tubulin-targeting