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

Erica Di Cesare1, Annalisa Verrico1, Andrea Miele1,2

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

Oncotarget
|February 5, 2017
PubMed

Insights

Arylthioindoles (ATIs) are novel tubulin polymerization inhibitors that arrest cancer cell division. These compounds display distinct efficacies and cellular fates, offering diverse therapeutic potential beyond current tubulin-targeting agents.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Tubulin-targeting agents are crucial in cancer therapy, inhibiting cell division by disrupting microtubule structures.
  • The cellular response to tubulin polymerization inhibitors is less understood compared to microtubule dynamics inhibitors.
  • Arylthioindoles (ATIs) are a novel class of tubulin inhibitors with demonstrated anti-cancer activity.

Purpose of the Study:

  • To comprehensively characterize the cellular response of cancer cell lines to five selected arylthioindoles (ATIs).
  • To investigate the differential efficacy and cell fate outcomes induced by ATIs with similar in vitro polymerization inhibitory activity.
  • To elucidate the molecular mechanisms underlying ATI-induced cell death, including mitotic apparatus damage, MCL-1 down-regulation, and caspase-3 activation.

Main Methods:

  • In vitro tubulin polymerization assays.
  • Cancer cell line viability assays.
  • Time-lapse microscopy for cell fate profiling.
  • Cytological analysis of mitotic apparatus.
  • Western blotting for MCL-1 and caspase-3 activation.

Main Results:

  • All tested ATIs effectively inhibited tubulin polymerization and arrested mitotic progression in cancer cells.
  • Distinct cell fate profiles were observed among ATIs, despite similar in vitro activity, highlighting differential in vivo efficacy.
  • ATIs induced varying degrees of mitotic apparatus damage, correlating with MCL-1 down-regulation and caspase-3 activation, determining cell death.
  • The study identified specific ATIs with distinct cytological phenotypes and downstream signaling events.

Conclusions:

  • Arylthioindoles exhibit diverse cellular responses and efficacies, offering a broader spectrum of tubulin-targeting cancer therapies.
  • Differential damage to the mitotic apparatus and subsequent apoptotic signaling pathways dictate the terminal cell fate.
  • These findings expand the understanding of tubulin inhibitor mechanisms and identify promising candidates for novel anti-cancer drug development.
Keywords:
caspase-3mitotic cell deathmitotic spindle microtubulestime-lapse imagingtubulin inhibitors

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