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Mitotic Cell Death Induction by Targeting the Mitotic Spindle with Tubulin-Inhibitory Indole Derivative Molecules

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Mitotic Cell Death Induction by Targeting the Mitotic Spindle with Tubulin-Inhibitory Indole Derivative Molecules www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 12), pp: 19738-19759 Research Paper Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules 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. INTRODUCTION proteins and other mitotic regulatory factors) also reduces cell proliferation and increases the death rate of cancer Microtubules (MTs) are tubulin polymers cells [7–10]. These approaches indicate that mitosis indispensable for a variety of cellular functions, including remains a valuable therapeutic target, encouraging efforts cell morphology and motility, intracellular transport, and to rationalize the design of mitosis-targeting molecules mitotic spindle assembly and dynamic activity. Mitotic and to understand the molecular bases of the cell response spindle impairment arrests cells in early mitotic stages to these molecules [11]. and can lead them to death. MTs are therefore among Although a variety of tumor types are sensitive the best-validated targets in cancer therapy. MT-targeting to MT-targeting agents, there are limitations to their agents have empirical therapeutic efficacy in a variety therapeutic use. First, the expression profile of genes of cancers [see 1-6 for reviews]. Targeting non-tubulin encoding MT-associated and MT-regulatory proteins found mitotic factors (e.g., mitotic kinases, kinesins, motor in different cancer types, and also within cells from a same www.impactjournals.com/oncotarget 19738 Oncotarget cancer, can synergize with, or antagonize, the effect of the (<400 kDa) compared to many MT-inhibitory drugs, such drugs [12–14]. Second, tumor cells can develop resistance as Vinblastine (VBL, 900 kDa), and their low molecular through diverse mechanisms [4, 15–17], involving not mass is expected to facilitate their delivery to target organs only the induction of efflux pump mechanisms implicated and tissues in animal models [34], iv) they inhibit cell in multidrug resistance, but also the presence of mutations growth in a broad array of cancer cell lines, including or differential expression of tubulin isotypes [18–21]. taxane-resistant derived lines [33–35]. The methods There is therefore a need to increase the molecular employed in those studies measured the global cell cycle repertoire of potentially effective drugs. profiles and the overall toxicity at the level of bulk cell Tubulin-targeting agents can either prevent MT population, but have limitations. Importantly, they neither polymerization or block their dynamic functions [1, 22]. identified the modes with which cell death occurred, nor In both cases dividing cells arrest in early mitosis with did they clarify whether ATIs induce generalized cell death a defective mitotic apparatus and can eventually undergo or whether cells become sensitized to death specifically death in mitosis, a molecularly distinct response from during mitosis. Here we take a step further and investigate other cell death pathways [8, 23–25]. Cells treated with in depth the response of cancer cell lines to five selected MT-targeting agents show variable propensity to undergo ATIs that proved promising in previous screening assays. mitotic cell death, even among cells from genetically Combined high-resolution immunofluorescence (IF) homogeneous cell populations [26–27]. Recent studies and single cell time-lapse recording methods are used to have sought to identify the determinants of mitotic pinpoint their specific features as mitotic inhibitors and death induction using in vivo imaging methods to follow cell death inducers, and contribute to identify effectors up mitotic cell fates at the single cell level. In the case required for the cell death response. of Taxol (TAX), the prototype MT-stabilizing drug, a framework defined the “competitive networks” model has RESULTS been formalized [28–30]. The model proposes that the heterogeneity in cell fates reflects the timing with which ATI compounds with similar in vitro tubulin- mitotic MT activity is blocked in individual cells: different binding activity arrest cell cycle progression cells would be endowed with a specific balance of pro- with differential effectiveness in human death and pro-mitotic factors, depending on their stage when TAX “hits” them. The model predicts that TAX- cancer cell lines dependent block of MT dynamics in cells with abundant The five ATIs examined in this work were designed cyclin B1 determines sustained mitotic arrest, allowing based on the structure of the Colchicine-binding site on time for the accumulation of pro-death factors that tubulin with molecular modeling back-up [37–38]. They eventually induce cell death. Below a critical cyclin B1 were originally conceived as successive derivatives from threshold, instead, mitotic arrest would not be sustained a common structural scaffold (schematically shown in for long enough to accumulate death factors, facilitating Figure 1A) and harbor substitutions at critical positions mitotic slippage with unsegregated or mis-segregating that confer improved metabolic stability and tubulin- chromosomes. c-Myc, BH3-only proteins and BCL-xL binding activity [details of design and synthesis, as well play critical roles in the final fate of TAX-treated cells as methods employed to measure tubulin polymerization [30]. In the case of drugs that inhibit MT assembly, the inhibition and competitive inhibition of labeled Colchicine links between the mechanisms of MT inhibition, the binding to tubulin, by each ATI, are given in 33-35]. The induction of mitotic arrest and the onset of mitotic death five molecules were previously examined in separate remain less well clarified. studies as members of large ATI subfamilies: they were In the last years, various strategies have been found to inhibit tubulin polymerization with comparable employed to design diversified molecules and expand IC50 at low micromolar concentrations in vitro and the molecular repertoire of anti-mitotic compounds. We competitively inhibited Colchicine binding to tubulin previously reported the development of a novel class of (in all cases above 75% inhibition [33–35], data are MT-targeting agents based on an arylthioindole scaffold summarized in Figure 1B for ease of comparison). All (ATI), which was designed to bind selectively the five ATIs inhibited cell growth in a variety of cancer cell Colchicine-binding site on tubulin. Colchicine binding lines, including multidrug resistant cells [33–35]. The inhibitors are regarded as promising compounds in recent underlying mechanism(s), however, were not examined studies [31–32]. Structure-activity relationship (SAR) and in depth. biological studies of ATIs [33–36] pinpointed potentially To gain insight into their mode of action in restricting interesting features: i) they competitively inhibit the cancer cell growth, we first compared their effects on cell 3 binding of [ H]Colchicine to tubulin in vitro; ii) they cycle progression in dose-response experiments. HeLa show good chemical and metabolic stability in microsomal cell cultures were treated with increasing concentrations fractions from the human and mouse liver, as well as in of each ATI for 24 hours (roughly
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