Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules.
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.
Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department of Biology and Biotechnology, Sapienza Università di Roma, Roma, Italy.
Erica
E
Di Cesare
Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department of Biology and Biotechnology, Sapienza Università di Roma, Roma, Italy.
Annalisa
A
Verrico
Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department of Biology and Biotechnology, Sapienza Università di Roma, Roma, Italy.|Present address: IRBM Science Park, Advent Srl, Pomezia, Italy.
Andrea
A
Miele
Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department of Biology and Biotechnology, Sapienza Università di Roma, Roma, Italy.|Present address: EMBL, Heidelberg, Germany.
Maria
M
Giubettini
Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department of Biology and Biotechnology, Sapienza Università di Roma, Roma, Italy.
Paola
P
Rovella
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technology, Sapienza Università di Roma, Roma, Italy.
Antonio
A
Coluccia
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technology, Sapienza Università di Roma, Roma, Italy.
Valeria
V
Famiglini
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technology, Sapienza Università di Roma, Roma, Italy.
Giuseppe
G
La Regina
Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department of Biology and Biotechnology, Sapienza Università di Roma, Roma, Italy.
Enrico
E
Cundari
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technology, Sapienza Università di Roma, Roma, Italy.
Romano
R
Silvestri
Institute of Molecular Biology and Pathology, CNR National Research Council, c/o Department of Biology and Biotechnology, Sapienza Università di Roma, Roma, Italy.
Patrizia
P
Lavia
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D059008:Time-Lapse Imaging / Q000379:methods; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators; D020169:Caspases
caspase-3; mitotic cell death; mitotic spindle microtubules; time-lapse imaging; tubulin inhibitors