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.

Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules / DI CESARE, Erica; Verrico, Annalisa; Miele, Andrea; Giubettini, Maria; Rovella, Paola; Coluccia, Antonio; Famiglini, Valeria; LA REGINA, Giuseppe; Cundari, Enrico; Silvestri, Romano; Lavia, Patrizia. - In: ONCOTARGET. - ISSN 1949-2553. - STAMPA. - 8:12(2017), pp. 19738-19759. [10.18632/oncotarget.14980]

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

DI CESARE, ERICA;VERRICO, ANNALISA;MIELE, ANDREA;GIUBETTINI, MARIA;COLUCCIA, Antonio;FAMIGLINI, VALERIA;LA REGINA, GIUSEPPE;SILVESTRI, Romano;
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.
2017
mitotic spindle microtubules; tubulin inhibitors; mitotic cell death; caspase-3; time-lapse imaging
01 Pubblicazione su rivista::01a Articolo in rivista
Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules / DI CESARE, Erica; Verrico, Annalisa; Miele, Andrea; Giubettini, Maria; Rovella, Paola; Coluccia, Antonio; Famiglini, Valeria; LA REGINA, Giuseppe; Cundari, Enrico; Silvestri, Romano; Lavia, Patrizia. - In: ONCOTARGET. - ISSN 1949-2553. - STAMPA. - 8:12(2017), pp. 19738-19759. [10.18632/oncotarget.14980]
File allegati a questo prodotto
File Dimensione Formato  
Di-Cesare_Mitotic_2017.pdf

accesso aperto

Note: Sul sito dell'Editore è riportato: "Oncotarget applies the Creative Commons Attribution 3.0 License (CC BY 3.0) to all works we publish"
Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 9.39 MB
Formato Adobe PDF
9.39 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/935705
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 19
  • ???jsp.display-item.citation.isi??? 19
social impact