Oncotarget

Research Papers:

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

Erica Di Cesare, Annalisa Verrico, Andrea Miele, Maria Giubettini, Paola Rovella, Antonio Coluccia, Valeria Famiglini, Giuseppe La Regina, Enrico Cundari, Romano Silvestri and Patrizia Lavia _

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Oncotarget. 2017; 8:19738-19759. https://doi.org/10.18632/oncotarget.14980

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Abstract

Erica Di Cesare1, Annalisa Verrico1, Andrea Miele1,2, Maria Giubettini1,3, Paola Rovella1, Antonio Coluccia4, Valeria Famiglini4, Giuseppe La Regina4, Enrico Cundari1, Romano Silvestri4, Patrizia Lavia1

1Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department of Biology and Biotechnology, Sapienza Università di Roma, Roma, Italy

2Present address: IRBM Science Park, Advent Srl, Pomezia, Italy

3Present address: EMBL, Heidelberg, Germany

4Istituto Pasteur Italia–Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technology, Sapienza Università di Roma, Roma, Italy

Correspondence to:

Patrizia Lavia, email: [email protected]

Keywords: mitotic spindle microtubules, tubulin inhibitors, mitotic 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 mitotic spindle, ultimately preventing cell division. The final fates of microtubule-inhibited cells are however often heterogeneous and difficult to predict. While recent work has provided insight into the cell response to inhibitors of microtubule dynamics (taxanes), the cell response to tubulin polymerization inhibitors remains less well characterized. Arylthioindoles (ATIs) are recently developed tubulin inhibitors. We previously identified ATI members that effectively inhibit tubulin polymerization in vitro and cancer cell growth in bulk cell viability assays. Here we characterise in depth the response of cancer cell lines to five selected ATIs. We find that all ATIs arrest mitotic progression, yet subsequently yield distinct cell fate profiles in time-lapse recording assays, indicating that molecules endowed with similar tubulin polymerization inhibitory activity in vitro can in fact display differential efficacy in living cells. Individual ATIs induce cytological phenotypes of increasing severity in terms of damage to the mitotic apparatus. That differentially triggers MCL-1 down-regulation and caspase-3 activation, and underlies the terminal fate of treated cells. Collectively, these results contribute to define the cell response to tubulin inhibitors and pinpoint potentially valuable molecules that can increase the molecular diversity of tubulin-targeting agents.


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