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Mitotic catastrophe

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https://www.readbyqxmd.com/read/29779163/discovering-simple-phenylboronic-acid-and-benzoxaborole-derivatives-for-experimental-oncology-phase-cycle-specific-inducers-of-apoptosis-in-a2780-ovarian-cancer-cells
#1
Mateusz Psurski, Agnieszka Łupicka-Słowik, Agnieszka Adamczyk-Woźniak, Joanna Wietrzyk, Andrzej Sporzyński
Objective The aim of the study was to evaluate the antiproliferative potential of simple phenylboronic acid and benzoxaborole derivatives as well as to provide preliminary insight into their mode of action in cancer cells in vitro. Methods The antiproliferative activity was assessed in five diverse cancer cell lines via the SRB method (sulforhodamine B) or MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method after 72 h of treatment. Further studies of the mechanism of action consisted of the influence of the compounds on cell cycle progression and apoptosis induction, which was assessed by flow cytometry, caspase-3 enzymatic activity, fluorescence microscopy and western blot analysis...
May 19, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29769307/orally-bioavailable-and-blood-brain-barrier-penetrating-atm-inhibitor-az32-radiosensitizes-intracranial-gliomas-in-mice
#2
Jeremy Karlin, Jasmine Allen, Syed F Ahmad, Gareth Hughes, Victoria Sheridan, Rajesh Odedra, Paul Farrington, Elaine B Cadogan, Lucy C Riches, Antonio Garcia-Trinidad, Andrew G Thomason, Bhavika Patel, Jennifer Vincent, Alan Lau, Kurt G Pike, Thomas A Hunt, Amrita Sule, Nicholas C K Valerie, Laura Biddlestone-Thorpe, Jenna Kahn, Jason M Beckta, Nitai Mukhopadhyay, Bernard Barlaam, Sebastien L Degorce, Jason Kettle, Nicola Colclough, Joanne Wilson, Aaron Smith, Ian P Barrett, Li Zheng, Tianwei Zhang, Yingchun Wang, Kan Chen, Martin Pass, Stephen T Durant, Kristoffer Valerie
Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited CNS bioavailability, thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain...
May 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29765534/bi2536-induces-mitotic-catastrophe-and-radiosensitization-in-human-oral-cancer-cells
#3
Chieh-Yuan Cheng, Chung-Ji Liu, Yu-Chuen Huang, Shu-Hua Wu, Hsu-Wei Fang, Yu-Jen Chen
BI2536 has been developed as a potential therapeutic agent for various cancers but not in oral cancer cells. Since BI2536 exhibits mitosis-regulating activity which are the most radiosensitive, we hypothesized that BI2536 might modulate the radiosensitivity of oral cancer cells. Human normal fibroblasts, oral cancer SAS, and OECM1 cells were treated with BI2536 (0-50 nM) and/or radiation (0-4 Gy). MTT assay, Liu's staining, flow cytometry, clonogenic assay, Annexin V/propidium iodide (PI) staining, western blot analysis, and small interfering RNA knockdown experiments were used to assess cell viability, morphology, cell cycle progression, radiation survival, and expression of regulatory proteins in vitro ...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29750898/mebendazole-exhibits-potent-anti-leukemia-activity-on-acute-myeloid-leukemia
#4
Licai He, Liuzhi Shi, Zhuanyun Du, He Huang, Rui Gong, Lan Ma, Lianjuan Chen, Shenmeng Gao, Jianxin Lyu, Haihua Gu
Acute myeloid leukemia (AML) is one of the most common types of acute leukemia in adults with the lowest survival rate of all leukemia. Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure. Thus, finding new drugs with anti-leukemia activities and minimal side effect is urgently needed. Here through screening more than 1000 drugs approved by the Food and Drug Administration (FDA) of United States, the antihelmintic drug mebendazole (MBZ) was found to inhibit the growth of AML cell lines (THP-1, U937, NB4 and K562) and bone marrow mononuclear cells (BM-MNCs) from AML patients at pharmacologically achievable concentrations...
May 8, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29713275/the-novel-small-molecule-stk899704-promotes-senescence-of-the-human-a549-nsclc-cells-by-inducing-dna-damage-responses-and-cell-cycle-arrest
#5
Chan-Woo Park, Yesol Bak, Min-Je Kim, Ganipisetti Srinivasrao, Joonsung Hwang, Nak K Sung, Bo Yeon Kim, Jae-Hyuk Yu, Jin Tae Hong, Do-Young Yoon
The novel synthetic compound designated STK899704 (PubChem CID: 5455708) suppresses the proliferation of a broad range of cancer cell types. However, the details of its effect on lung cancer cells are unclear. We investigated the precise anticancer effect of STK899704 on senescence and growth arrest of A549 human non-small cell lung cancer (NSCLC) cells. STK899704 affected NSCLC cell cycle progression and decreased cell viability in a dose-dependent manner. Immunofluorescence staining revealed that STK899704 destabilized microtubules...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29689640/haploid-genetic-screens-identify-genetic-vulnerabilities-to-microtubule-targeting-agents
#6
Nora M Gerhards, Vincent A Blomen, Merve Mutlu, Joppe Nieuwenhuis, Denise Howald, Charlotte Guyader, Jos Jonkers, Thijn R Brummelkamp, Sven Rottenberg
The absence of biomarkers to accurately predict anti-cancer therapy response remains a major obstacle in clinical oncology. We applied a genome-wide loss-of-function screening approach in human haploid cells to characterize genetic vulnerabilities to classical microtubule-targeting agents. Using docetaxel and vinorelbine, two well-established chemotherapeutic agents, we sought to identify genetic alterations sensitizing human HAP1 cells to these drugs. Despite the fact that both drugs act on microtubules, a set of distinct genes were identified whose disruption affect drug sensitivity...
April 24, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29679654/the-vanillin-derivative-6-bromine-5-hydroxy-4-methoxybenzaldehyde-induces-aberrant-mitotic-progression-and-enhances-radio-sensitivity-accompanying-suppression-the-expression-of-plk1-in-esophageal-squamous-cell-carcinoma
#7
Meng-Meng Gu, Ming Li, Dexuan Gao, Lang-Huan Liu, Yue Lang, Si-Ming Yang, Hongling Ou, Bo Huang, Ping-Kun Zhou, Zeng-Fu Shang
Esophageal squamous cell carcinoma (ESCC) is the most common form of esophageal cancer in China. Since chemotherapy is the standard clinical intervention for advanced ESCC, the development of highly effective and minimal/non-toxic drugs is essential to improve the clinical outcome and prognosis of the patients. A novel derivative of vanillin, 6-bromine-5-hydroxy-4-methoxybenzaldehyde (BVAN08), has been recently reported to activate different cell death pathways in cancer cells. In this study, we demonstrate that BVAN08 exhibits a potent anti-proliferation effect on ESCC cells (TE-1 and ECA-109) by inhibiting the expression of PLK1, an important mitotic kinase...
April 18, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29672918/ionizing-radiation-but-not-ultraviolet-radiation-induces-mitotic-catastrophe-in-mouse-epidermal-keratinocytes-with-aberrant-cell-cycle-checkpoints
#8
Ming Wang, QingXiang Gao, Xu Teng, MeiPing Pan, TianMiao Lin, GuiXuan Zhou, BenHua Xu, ZhiCao Yue
Ultraviolet radiation (UVR) and ionizing radiation (IR) are common genotoxic stresses that damage human skin, although the specific damages to the genomic DNA are different. Here we show that in the mouse glabrous skin, both UVR and IR induce DNA damage, cell cycle arrest, and condensed cell nuclei. However, only IR induces mitotic catastrophe (MC) in the epidermis. This is because UVR induces a complete blockage of pRB phosphorylation and cell cycle arrest in the G1 phase, whereas pRB phosphorylation remains positive in a significant portion of the epidermal keratinocytes following IR exposure...
April 19, 2018: Experimental Dermatology
https://www.readbyqxmd.com/read/29661912/microtubule-end-tethering-of-a-processive-kinesin-8-motor-kif18b-is-required-for-spindle-positioning
#9
Toni McHugh, Agata A Gluszek, Julie P I Welburn
Mitotic spindle positioning specifies the plane of cell division during anaphase. Spindle orientation and positioning are therefore critical to ensure symmetric division in mitosis and asymmetric division during development. The control of astral microtubule length plays an essential role in positioning the spindle. In this study, using gene knockout, we show that the kinesin-8 Kif18b controls microtubule length to center the mitotic spindle at metaphase. Using in vitro reconstitution, we reveal that Kif18b is a highly processive plus end-directed motor that uses a C-terminal nonmotor microtubule-binding region to accumulate at growing microtubule plus ends...
April 16, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29643118/tfiih-is-highly-dynamic-during-zygotic-genome-activation-in-drosophila-and-its-depletion-causes-catastrophic-mitosis
#10
Grisel Cruz-Becerra, Sarai Valerio-Cabrera, Mandy Juárez, Alyeri Bucio-Mendez, Mario Zurita
In Drosophila zygotic genome activation occurs in pre-blastoderm embryos during rapid mitotic divisions. How the transcription machinery is coordinated to achieve this goal in a very brief time span is still poorly understood. TFIIH is fundamental for transcription initiation by RNA polymerase II (RNAPII). Herein, we show the in vivo dynamics of TFIIH at the onset of transcription in Drosophila embryos. TFIIH shows an oscillatory behaviour between the nucleus and cytoplasm. TFIIH foci are observed from interphase to metaphase, and co-localize with the RNAPII phosphorylated at serine 5 (RNAPIIS5P) at prophase, suggesting that transcription overlaps with the first mitotic phases...
April 11, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29628886/u1-snrnp-alteration-and-neuronal-cell-cycle-reentry-in-alzheimer-disease
#11
REVIEW
Bing Bai
The aberrancy of U1 small nuclear ribonucleoprotein (snRNP) complex and RNA splicing has been demonstrated in Alzheimer's disease (AD). Importantly, the U1 proteopathy is AD-specific, widespread and early-occurring, thus providing a very unique clue to the AD pathogenesis. The prominent feature of U1 histopathology is its nuclear depletion and redistribution in the neuronal cytoplasm. According to the preliminary data, the initial U1 cytoplasmic distribution pattern is similar to the subcellular translocation of the spliceosome in cells undergoing mitosis...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29605721/combined-inhibition-of-atr-and-wee1-as-a-novel-therapeutic-strategy-in-triple-negative-breast-cancer
#12
Juan Jin, Hehui Fang, Fang Yang, Wenfei Ji, Nan Guan, Zijia Sun, Yaqin Shi, Guohua Zhou, Xiaoxiang Guan
Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that poses a clinical challenge. Thus, new therapy strategies are urgently needed. The selective WEE1 inhibitor, AZD1775, has shown strong anti-proliferative effects on a variety of tumors. Here, we first demonstrate that inhibition of ATR by selective inhibitor AZD6738 can enhance AZD1775-caused growth inhibition in TNBC. Our results show that the enhanced cell death is attributed to repressed DNA damage repair and excessive replication stress, thereby causing increased DNA damage reflected by accumulation of the DNA double-strand-break marker γH2AX...
March 28, 2018: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29599321/induction-of-mitotic-catastrophe-in-human-cervical-cancer-cells-after-administration-of-aloe-emodin
#13
Wojciech Trybus, Teodora Król, Ewa Trybus, Anna Stachurska, Anna Kopacz-Bednarska, Grzegorz Król
BACKGROUND: Aloe-emodin is an anthraquinone with potential pharmacological properties, including numerous antitumor properties. The purpose of the study was to determine whether aloe-emodin induces mitotic death in cervical cancer cells. MATERIALS AND METHODS: Analysis of morphological changes as surrogate mitotic death indicators in HeLa cells was carried out using optical, fluorescence and electron microscopy. Viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide reduction assay...
April 2018: Anticancer Research
https://www.readbyqxmd.com/read/29568361/colorectal-cancer-cells-require-glycogen-synthase-kinase-3%C3%AE-for-sustaining-mitosis-via-translocated-promoter-region-tpr-dynein-interaction
#14
Firli R P Dewi, Takahiro Domoto, Masaharu Hazawa, Akiko Kobayashi, Takayuki Douwaki, Toshinari Minamoto, Richard W Wong
Glycogen synthase kinase (GSK) 3β, which mediates fundamental cellular signaling pathways, has emerged as a potential therapeutic target for many types of cancer including colorectal cancer (CRC). During mitosis, GSK3β localizes in mitotic spindles and centrosomes, however its function is largely unknown. We previously demonstrated that translocated promoter region (TPR, a nuclear pore component) and dynein (a molecular motor) cooperatively contribute to mitotic spindle formation. Such knowledge encouraged us to investigate putative functional interactions among GSK3β, TPR, and dynein in the mitotic machinery of CRC cells...
March 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29562589/an-interplay-between-senescence-apoptosis-and-autophagy-in-glioblastoma-multiforme-role-in-pathogenesis-and-therapeutic-perspective
#15
REVIEW
Elzbieta Pawlowska, Joanna Szczepanska, Magdalena Szatkowska, Janusz Blasiak
Autophagy, cellular senescence, programmed cell death and necrosis are key responses of a cell facing a stress. These effects are partly interconnected, but regulation of their mutual interactions is not completely clear. That regulation seems to be especially important in cancer cells, which have their own program of development and demand more nutrition and energy than normal cells. Glioblastoma multiforme (GBM) belongs to the most aggressive and most difficult to cure cancers, so studies on its pathogenesis and new therapeutic strategies are justified...
March 17, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29541386/atp-competitive-plk1-inhibitors-induce-caspase-3-mediated-plk1-cleavage-and-activation-in-hematopoietic-cell-lines
#16
Maeva Dufies, Damien Ambrosetti, Sonia Boulakirba, Anne Calleja, Coline Savy, Nathan Furstoss, Marwa Zerhouni, Julien Parola, Lazaro Aira-Diaz, Sandrine Marchetti, Francois Orange, Sandra Lacas-Gervais, Frederic Luciano, Arnaud Jacquel, Guillaume Robert, Gilles Pagès, Patrick Auberger
Polo-like kinases (Plks) define a highly conserved family of Ser/Thr kinases with crucial roles in the regulation of cell division. Here we show that Plk1 is cleaved by caspase 3, but not by other caspases in different hematopoietic cell lines treated with competitive inhibitors of the ATP-binding pocket of Plk1. Intriguingly, Plk1 was not cleaved in cells treated with Rigosertib, a non-competitive inhibitor of Plk1, suggesting that binding of the inhibitor to the ATP binding pocket of Plk1 triggers a conformational change and unmasks a cryptic caspase 3 cleavage site on the protein...
February 16, 2018: Oncotarget
https://www.readbyqxmd.com/read/29515122/pan-class-i-pi3-kinase-inhibitor-bkm120-induces-mek1-2-dependent-mitotic-catastrophe-in-non-hodgkin-lymphoma-leading-to-apoptosis-or-polyploidy-determined-by-bax-bak-and-p53
#17
Anja Müller, Bernd Gillissen, Antje Richter, Anja Richter, Cindrilla Chumduri, Peter T Daniel, Christian W Scholz
Constitutive signaling of PI3K/Akt/mTOR plays a prominent role in malignant transformation and progression of B-cell non-Hodgkin lymphomas (B-NHL) underscoring the need for PI3K targeted therapies. The pan-class I PI3-kinase inhibitor BKM120 has shown preclinical activity in distinct malignancies and is currently tested in clinical trials. Intratumor heterogeneity is an intrinsic property of cancers that contributes to drug resistance and tumor recurrence. Here, we demonstrate that inhibition of PI3-kinases by BKM120 attenuates growth and survival of B-NHL cell lines by inducing mitotic arrest with subsequent induction of intrinsic apoptosis...
March 7, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29497138/anti-mitotic-chemotherapeutics-promote-apoptosis-through-tl1a-activated-death-receptor-3-in-cancer-cells
#18
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
https://www.readbyqxmd.com/read/29493085/overcoming-resistance-to-mitochondrial-apoptosis-by-bzml-induced-mitotic-catastrophe-is-enhanced-by-inhibition-of-autophagy-in-a549-taxol-cells
#19
Zhaoshi Bai, Meiqi Gao, Xiaobo Xu, Huijuan Zhang, Jingwen Xu, Qi Guan, Qing Wang, Jianan Du, Zhengqiang Li, Daiying Zuo, Weige Zhang, Yingliang Wu
OBJECTIVES: Our previous in vitro study showed that 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) is a novel colchicine binding site inhibitor with potent anti-cancer activity against apoptosis resistance in A549/Taxol cells through mitotic catastrophe (MC). However, the mechanisms underlying apoptosis resistance in A549/Taxol cells remain unknown. To clarify these mechanisms, in the present study, we investigated the molecular mechanisms of apoptosis and autophagy, which are closely associated with MC in BZML-treated A549 and A549/Taxol cells...
March 1, 2018: Cell Proliferation
https://www.readbyqxmd.com/read/29472538/hdac1-and-hdac2-integrate-checkpoint-kinase-phosphorylation-and-cell-fate-through-the-phosphatase-2a-subunit-pr130
#20
Anja Göder, Claudia Emmerich, Teodora Nikolova, Nicole Kiweler, Maria Schreiber, Toni Kühl, Diana Imhof, Markus Christmann, Thorsten Heinzel, Günter Schneider, Oliver H Krämer
Checkpoint kinases sense replicative stress to prevent DNA damage. Here we show that the histone deacetylases HDAC1/HDAC2 sustain the phosphorylation of the checkpoint kinases ATM, CHK1 and CHK2, activity of the cell cycle gatekeeper kinases WEE1 and CDK1, and induction of the tumour suppressor p53 in response to stalled DNA replication. Consequently, HDAC inhibition upon replicative stress promotes mitotic catastrophe. Mechanistically, HDAC1 and HDAC2 suppress the expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2 (PP2A)...
February 22, 2018: Nature Communications
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