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Spindle Poisons

Sofia-Eléna Motuhi, Omid Feizbakhsh, Béatrice Foll-Josselin, Blandine Baratte, Claire Delehouzé, Arnaud Cousseau, Xavier Fant, Jeannette Chloë Bulinski, Claude Elisabeth Payri, Sandrine Ruchaud, Mohamed Mehiri, Stéphane Bach
The marine α-pyrone macrolide neurymenolide A was previously isolated from the Fijian red macroalga, Neurymenia fraxinifolia , and characterized as an antibacterial agent against antibiotic-resistant strains that also exhibited moderate cytotoxicity in vitro against cancer cell lines. This compound was also shown to exhibit allelopathic effects on Scleractinian corals. However, to date no mechanism of action has been described in the literature. The present study showed, for the first time, the isolation of neurymenolide A from the New Caledonian Rhodophyta, Phacelocarpus neurymenioides ...
February 1, 2019: Marine Drugs
Thomas Efferth, Mohamed E M Saeed, Onat Kadioglu, Ean-Jeong Seo, Samira Shirooie, Armelle T Mbaveng, Seyed Mohammad Nabavi, Victor Kuete
Cancer chemotherapy is frequently hampered by drug resistance. Concepts to combine anticancer drugs with different modes of action to avoid the development of resistance did not provide the expected success in the past, because tumors can be simultaneously non-responsive to many drugs (e.g. the multidrug resistance phenotype). However, tumors may be specifically hypersensitive to other drugs - a phenomenon also termed collateral sensitivity. This seems to be a general biological mechanism, since it also occurs in drug-resistant Escherichia coli and Saccharomyces cerevisiae...
January 29, 2019: Biotechnology Advances
Shivangi Paliwal, Robert Wheeler, Tom D Wolkow
The DNA structure checkpoint protein Rad26ATRIP is also required for an interphase microtubule damage response. This checkpoint delays spindle pole body separation and entry into mitosis following treatment of cells with microtubule poisons. This checkpoint requires cytoplasmic Rad26ATRIP , which is compromised by the rad26:4A allele that inhibits cytoplasmic accumulation of Rad26ATRIP following microtubule damage. The rad26::4a allele also disrupts minichromosome stability and cellular morphology, suggesting that the interphase microtubule damage checkpoint pathway operates in an effort to maintain chromosome stability and proper cell shape...
September 2018: Molecular Biology Research Communications
Takehiko Nohmi
Exposure to chemical agents is an inevitable consequence of modern society; some of these agents are hazardous to human health. The effects of chemical carcinogens are of great concern in many countries, and international organizations, such as the World Health Organization, have established guidelines for the regulation of these chemicals. Carcinogens are currently categorized into two classes, genotoxic and non-genotoxic carcinogens, which are subject to different regulatory policies. Genotoxic carcinogens are chemicals that exert carcinogenicity via the induction of mutations...
October 2018: Toxicological Research
Edwige Kasper, Emilie Angot, Elodie Colasse, Lionel Nicol, Jean-Christophe Sabourin, Sahil Adriouch, Yann Lacoume, Camille Charbonnier, Sabine Raad, Thierry Frebourg, Jean-Michel Flaman, Gaëlle Bougeard
INTRODUCTION: Li-Fraumeni syndrome (LFS), due to TP53 germline mutations, is characterised by a remarkably high incidence of multiple primary cancers (MPCs), and the key role of p53 in response to DNA damage questions the contribution of anticancer treatments to MPCs development. MATERIALS AND METHODS: We first evaluated genotoxicity of X-rays and different classes of conventional chemotherapies, thanks to genotoxicity assays, based on the measurement of transcriptional response to DNA damage and performed in murine splenocytes, either exposed ex vivo or extracted from exposed mice...
September 2018: European Journal of Cancer
Ana Rita R Maia, Simon Linder, Ji-Ying Song, Chantal Vaarting, Ute Boon, Colin E J Pritchard, Arno Velds, Ivo J Huijbers, Olaf van Tellingen, Jos Jonkers, René H Medema
BACKGROUND: Chromosomal instability (CIN) is a common trait of cancer characterised by the continuous gain and loss of chromosomes during mitosis. Excessive levels of CIN can suppress tumour growth, providing a possible therapeutic strategy. The Mps1/TTK kinase has been one of the prime targets to explore this concept, and indeed Mps1 inhibitors synergise with the spindle poison docetaxel in inhibiting the growth of tumours in mice. METHODS: To investigate how the combination of docetaxel and a Mps1 inhibitor (Cpd-5) promote tumour cell death, we treated mice transplanted with BRCA1-/- ;TP53-/- mammary tumours with docetaxel and/or Cpd-5...
June 2018: British Journal of Cancer
Chen Qi, Xin Wang, Zhirong Shen, She Chen, Hong Yu, Noelle Williams, Gelin Wang
The commonly used antimitotic chemotherapeutic agents such as taxol and vinblastine arrest cell cycle progression by disrupting mitotic spindles, and cause cancer cells to undergo apoptosis through 'mitotic catastrophe'. The molecular mechanisms by which these drugs induce apoptosis and their relevance to clinical efficacy are not known. Facilitated by a new spindle poison diazonamide, we found that apoptosis induced by these agents requires death receptor 3 (DR3). Mitotic arrest by these agents induces lysosome-dependent secretion of the DR3 ligand, TL1A...
May 2018: Cell Research
Claudia Abbruzzese, Giada Catalogna, Enzo Gallo, Simona di Martino, Anna M Mileo, Mariantonia Carosi, Vincenzo Dattilo, Silvia Schenone, Francesca Musumeci, Patrizia Lavia, Nicola Perrotti, Rosario Amato, Marco G Paggi
Glioblastoma multiforme (GBM) is the deadliest brain tumor. State-of-art GBM therapy often fails to ensure control of a disease characterized by high frequency of recurrences and progression. In search for novel therapeutic approaches, we assayed the effect of compounds from a cancer drug library on the ADF GBM cell line, establishing their elevated sensitivity to mitotic spindle poisons. Our previous work showed that the effectiveness of the spindle poison paclitaxel in inhibiting cancer cell growth was dependent on the expression of RANBP1, a regulatory target of the serine/threonine kinase SGK1...
December 19, 2017: Oncotarget
Yu Liu, Xiao Du, Shuting Zhang, Yang Liu, Qiaoling Zhang, Qi Yin, Michael A McNutt, Yuxin Yin
The spindle assembly checkpoint (SAC) restrains anaphase progression to ensure all chromosomes attach properly to the spindle. Although SAC timing has been extensively investigated in mitosis, its mechanism of regulation in interphase is unclear. We report that PTEN functions as a crucial activator of SAC timing and protects chromosome segregation under both spindle poison treated and untreated conditions. We show that PTEN physically interacts with MAD1 and promotes its dimerization and localization in the nuclear pore...
November 17, 2017: Oncotarget
Chiara Cremolini, Filippo Pietrantonio, Gianluca Tomasello, Vincenzo Dadduzio, Roberto Moretto, Federica Morano, Marta Schirripa, Carlotta Antoniotti, Giovanni Fucà, Francesca Bergamo, Daniele Rossini, Federico Nichetti, Stamatia Ziampiri, Michele Ghidini, Federica Marmorino, Michele Prisciandaro, Alfredo Falcone, Filippo De Braud, Fotios Loupakis, Sara Lonardi
Background: BRAF V600E mutation defines a specific colorectal cancer (CRC) subgroup with poor prognosis. Promising preclinical data showed synthetically lethal activity of mitotic spindle poisons on BRAF- mutated and BRAF -like CRC models. We designed a phase II trial to test the activity of vinorelbine in patients with BRAF V600E mutated metastatic CRC (mCRC). Patients and methods: Patients progressed to or not deemed eligible for standard treatments received oral (60 mg/sqm) or intravenous (25 mg/sqm) vinorelbine, on days 1 and 8 every 21 days...
2017: ESMO Open
Dandan Chen, Xin Li, Xiaoyun Liu, Xiaoyu Liu, Xiuying Jiang, Juan Du, Qian Wang, Yuanjing Liang, Wei Ma
NRH: quinone oxidoreductase 2 (NQO2) is a cytosolic and ubiquitously expressed flavoprotein that catalyzes the two-electron reduction of quinone to hydroquinones. Herein, we assessed the protein expression, subcellular localization, and possible functions of NQO2 in mouse oocyte meiotic maturation and embryo development. Western blot analysis detected high and stable protein expression of NQO2 in mouse oocytes during meiotic progression. Immunofluorescence illustrated NQO2 distribution on nuclear membrane, chromosomes, and meiotic spindles...
October 1, 2017: Biology of Reproduction
Dana N Reinemann, Emma G Sturgill, Dibyendu Kumar Das, Miriam Steiner Degen, Zsuzsanna Vörös, Wonmuk Hwang, Ryoma Ohi, Matthew J Lang
During cell division, the mitotic kinesin-5 Eg5 generates most of the force required to separate centrosomes during spindle assembly. However, Kif15, another mitotic kinesin, can replace Eg5 function, permitting mammalian cells to acquire resistance to Eg5 poisons. Unlike Eg5, the mechanism by which Kif15 generates centrosome separation forces is unknown. Here we investigated the mechanical properties and force generation capacity of Kif15 at the single-molecule level using optical tweezers. We found that the non-motor microtubule-binding tail domain interacts with the microtubule's E-hook tail with a rupture force higher than the stall force of the motor...
September 25, 2017: Current Biology: CB
Christine A Mills, Aussie Suzuki, Anthony Arceci, Jin Yao Mo, Alex Duncan, Edward D Salmon, Michael J Emanuele
The mitotic spindle is composed of dynamic microtubules and associated proteins that together direct chromosome movement during mitosis. The spindle plays a vital role in accurate chromosome segregation fidelity and is a therapeutic target in cancer. Nevertheless, the molecular mechanisms by which many spindle-associated proteins function remains unknown. The <u>nu</u>cleolar and <u>s</u>pindle-<u>a</u>ssociated <u>p</u>rotein NUSAP1 is a microtubule-binding protein implicated in spindle stability and chromosome segregation...
October 20, 2017: Journal of Biological Chemistry
Pauline Gilson, Fernando Josa-Prado, Claire Beauvineau, Delphine Naud-Martin, Laetitia Vanwonterghem, Florence Mahuteau-Betzer, Alexis Moreno, Pierre Falson, Laurence Lafanechère, Véronique Frachet, Jean-Luc Coll, Jose Fernando Díaz, Amandine Hurbin, Benoit Busser
Despite the emergence of targeted therapies and immunotherapy, chemotherapy remains the gold-standard for the treatment of most patients with solid malignancies. Spindle poisons that interfere with microtubule dynamics are commonly used in chemotherapy drug combinations. However, their troublesome side effects and the emergence of chemoresistance highlight the need for identifying alternative agents. We performed a high throughput cell-based screening and selected a pyrrolopyrimidine molecule (named PP-13)...
August 31, 2017: Scientific Reports
Shivangi Agarwal, Dileep Varma
A colossal amount of basic research over the past few decades has provided unprecedented insights into the highly complex process of cell division. There is an ever-expanding catalog of proteins that orchestrate, participate and coordinate in the exquisite processes of spindle formation, chromosome dynamics and the formation and regulation of kinetochore microtubule attachments. Use of classical microtubule poisons has still been widely and often successfully used to combat a variety of cancers, but their non-selective interference in other crucial physiologic processes necessitate the identification of novel druggable components specific to the cell cycle/division pathway...
September 2017: Endocrine-related Cancer
Thomas J Kucharski, Paul E Minshall, Mohamed Moustafa-Kamal, Andrew S Turnell, Jose G Teodoro
The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets substrates for degradation to promote mitotic progression. Here, we show that the DNA damage response protein 53BP1 contains conserved KEN boxes that are required for APC/C-dependent degradation in early mitosis. Mutation of the 53BP1 KEN boxes stabilized the protein and extended mitotic duration, whereas 53BP1 knockdown resulted in a shorter and delayed mitosis. Loss of 53BP1 increased APC/C activity, and we show that 53BP1 is a direct APC/C inhibitor...
February 21, 2017: Cell Reports
Ahmed Sk Al-Khafaji, Michael Pa Davies, Janet M Risk, Michael W Marcus, Maria Koffa, John R Gosney, Richard J Shaw, John K Field, Triantafillos Liloglou
BACKGROUND: Taxanes are mitotic poisons widely used in the treatment of non-small cell lung cancer (NSCLC), however, little is known about potential molecular modulators of response to these compounds. Aurora B (AURKB) is a critical regulator of the mitotic spindle assembly, previously shown overexpressed in NSCLC. Here we investigated the hypothesis that AURKB expression modulates the efficacy of taxanes in NSCLC cells. METHODS: AURKB mRNA expression was determined by qPCR in 132 frozen NSCLC tissues and nine NSCLC cell lines...
February 28, 2017: British Journal of Cancer
Joanne M Elloway, Alexandra K Davies, Julie E Hayes, Ann T Doherty
The detection of aneugenic chemicals is important due to the implications of aneuploidy for human health. Aneuploidy can result from chromosome loss or nondisjunction due to chromosome mis-segregation at anaphase. Frequently, aneugens are detected using the in vitro micronucleus assay (IVM), with either centromere or kinetochore labeling. However, this method does not consider nondisjunction, the suggested predominant mechanism of spindle poison induced aneugenicity in primary human lymphocytes. Therefore, the IVM may be relatively insensitive in detecting aneuploidy...
May 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Barbara Di Fiore, Claudia Wurzenberger, Norman E Davey, Jonathon Pines
The Spindle Assembly Checkpoint (SAC) ensures genomic stability by preventing sister chromatid separation until all chromosomes are attached to the spindle. It catalyzes the production of the Mitotic Checkpoint Complex (MCC), which inhibits Cdc20 to inactivate the Anaphase Promoting Complex/Cyclosome (APC/C). Here we show that two Cdc20-binding motifs in BubR1 of the recently identified ABBA motif class are crucial for the MCC to recognize active APC/C-Cdc20. Mutating these motifs eliminates MCC binding to the APC/C, thereby abolishing the SAC and preventing cells from arresting in response to microtubule poisons...
December 15, 2016: Molecular Cell
Corinne Quadalti, Cesare Galli, Giovanna Lazzari
The implementation of the REACH regulation has imposed the urgent need of developing alternative testing methods to screen large number of compounds more quickly and at lower costs. In this study, a battery of tests, suitable for reproductive toxicology testing, was developed with the objective of detecting the mechanism of action of estrogenic and xenoestrogenic compounds. With this aim, two compounds known for their estrogenic activity, diethylstilbestrol and 17β-estradiol, were used to set up four different in vitro tests: 1) bovine oocyte in vitro maturation assay, 2) bovine preimplantation embryo in vitro culture assay and 3) MCF-7 and 4) BALB/3T3 cell lines proliferation and cytotoxicity assay, respectively...
December 2016: Environmental Toxicology and Pharmacology
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