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https://www.readbyqxmd.com/read/28415717/the-imidazoacridinone-c-1311-induces-p53-dependent-senescence-or-p53-independent-apoptosis-and-sensitizes-cancer-cells-to-radiation
#1
Anna Skwarska, Shaliny Ramachandran, Grzegorz Dobrynin, Katarzyna B Leszczynska, Ester M Hammond
C-1311 is a small molecule, which has shown promise in a number of pre-clinical and clinical studies. However, the biological response to C-1311 exposure is complicated and has been reported to involve a number of cell fates. Here, we investigated the molecular signaling which determines the response to C-1311 in both cancer and non-cancer cell lines. For the first time we demonstrate that the tumor suppressor, p53 plays a key role in cell fate determination after C-1311 treatment. In the presence of wild-type p53, cells exposed to C-1311 entered senescence...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415610/the-tubulin-inhibitor-mg-2477-induces-autophagy-regulated-cell-death-ros-accumulation-and-activation-of-foxo3-in-neuroblastoma
#2
Judith Hagenbuchner, Lorena Lungkofler, Ursula Kiechl-Kohlendorfer, Giampietro Viola, Maria Grazia Ferlin, Michael J Ausserlechner, Petra Obexer
Neuroblastoma is the most frequent extra-cranial solid tumor in children with still high mortality in stage M. Here we studied the tubulin-inhibitor MG-2477 as a possible therapeutic agent for neuroblastoma therapy and uncovered that MG-2477 induces death in neuroblastoma cells independent of PKB-activation status and stage. MG-2477 triggers within 30 minutes extensive autophagosome-formation that finally leads to cell death associated with mitotic catastrophe. Autophagy is critical for MG-2477-induced death and is regulated by the BH3-only protein PMAIP1/NOXA which sequesters the anti-apoptotic BCL2-protein BCLXL and thereby displaces and activates the autophagy-regulator BECN1/beclin1...
March 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28409150/mitotic-catastrophe-in-bc3h1-cells-following-yessotoxin-exposure
#3
Mónica Suárez Korsnes, Reinert Korsnes
The marine toxin yessotoxin (YTX) can cause various cytotoxic effects depending on cell type and cell line. It is well known to trigger distinct mechanisms for programmed cell death which may overlap or cross-talk. The present contribution provides the first evidence that YTX can cause genotoxicity and induce mitotic catastrophe which can lead to different types of cell death. This work also demonstrates potential information gain from non-intrusive computer-based tracking of many individual cells during long time...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/28394338/parp-inhibitors-enhance-replication-stress-and-cause-mitotic-catastrophe-in-mycn-dependent-neuroblastoma
#4
V Colicchia, M Petroni, G Guarguaglini, F Sardina, M Sahún-Roncero, M Carbonari, B Ricci, C Heil, C Capalbo, F Belardinilli, A Coppa, G Peruzzi, I Screpanti, P Lavia, A Gulino, G Giannini
High-risk and MYCN-amplified neuroblastomas are among the most aggressive pediatric tumors. Despite intense multimodality therapies, about 50% of these patients succumb to their disease, making the search for effective therapies an absolute priority. Due to the important functions of poly (ADP-ribose) polymerases, PARP inhibitors have entered the clinical settings for cancer treatment and are being exploited in a variety of preclinical studies and clinical trials. PARP inhibitors based combination schemes have also been tested in neuroblastoma preclinical models with encouraging results...
April 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28365670/the-impact-of-concentration-and-administration-time-on-the-radiomodulating-properties-of-undecylprodigiosin-in-vitro
#5
Sandra Petrović, Vesna Vasić, Tatjana Mitrović, Saša Lazović, Andreja Leskovac
Undecylprodigiosin pigment (UPP) is reported to display cytotoxic activity towards various types of tumours. Nevertheless, its efficacy in modifying the cellular response to ionising radiation is still unknown. In this study, the radiomodulating effects of UPP were investigated. The effects of UPP were assessed in vitro by treating cultures of human peripheral blood with UPP and ionising radiation using two treatment regimens, the UPP pre-irradiation treatment and UPP post-irradiation treatment. The activity of UPP was investigated evaluating its effects on the radiation-induced micronuclei formation, cell proliferation, and induction of apoptosis...
March 1, 2017: Arhiv za Higijenu Rada i Toksikologiju
https://www.readbyqxmd.com/read/28353363/does-chronomodulated-radiotherapy-improve-pathological-response-in-locally-advanced-rectal-cancer
#6
Tim Squire, Grant Buchanan, David Rangiah, Ian Davis, Desmond Yip, Yu Jo Chua, Tyvin Rich, Hany Elsaleh
The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy...
2017: Chronobiology International
https://www.readbyqxmd.com/read/28299790/tc-mps1-12-a-novel-mps1-inhibitor-suppresses-a-growth-of-hepatocellular-carcinoma-cells-via-accumulated-chromosomal-instability
#7
Minji Choi, Yoo Hong Min, Jaehyuk Pyo, Chang-Woo Lee, Chang-Young Jang, Ja-Eun Kim
BACKGROUND AND PURPOSE: Chromosomal instability is not only a hallmark of cancer, but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed...
March 15, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28243113/efficacy-of-eribulin-in-breast-cancer-a-short-report-on-the-emerging-new-data
#8
REVIEW
Gelareh Eslamian, Caroline Wilson, Robin J Young
Eribulin is a novel microtubule-targeting agent that is approved for the treatment of patients with locally advanced or metastatic breast cancer who have previously received treatment with an anthracycline and a taxane in either the adjuvant or metastatic setting. Eribulin induces mitotic catastrophe leading to cell death but has other important antitumor effects, including reversal of epithelial-mesenchymal transition and remodeling of the tumor vasculature. Eribulin was licensed for the treatment of advanced breast cancer based on results from two large randomized Phase III clinical trials...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28202528/distinct-levels-of-radioresistance-in-lgr5-colonic-epithelial-stem-cells-versus-lgr5-small-intestinal-stem-cells
#9
Guoqiang Hua, Chu Wang, Yan Pan, Zhaoshi Zeng, Sang Gyu Lee, Maria Laura Martin, Adriana Haimovitz-Friedman, Zvi Fuks, Philip B Paty, Richard Kolesnick
Although small and large intestines possess seemingly similar Wnt-driven leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)(+) adult epithelial stem cells, we report here that the two organs exhibit distinct mechanisms of tissue response to ionizing radiation. Employing Lgr5-lacZ transgenic mice and Lgr5 in situ hybridization, we found colonic epithelial stem cells (CESC) markedly more radioresistant in vivo than small intestinal crypt base columnar stem cells (CBC; D0 = 6.0 ± 0.3 Gy vs. 1...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28195671/trachycladines-and-analogues-synthesis-and-evaluation-of-anticancer-activity
#10
Zisis V Peitsinis, Achilleas G Mitrakas, Eirini A Nakiou, Dafni A Melidou, Dimitra Kalamida, Christos Kakouratos, Michael I Koukourakis, Alexandros E Koumbis
The synthesis of four new analogues of marine nucleoside trachycladine A was accomplished by direct regio- and stereoselective Vorbrüggen glycosylations of 2,6-dichloropurine and 2-chloropurine with a d-ribose-derived chiron. Naturally occurring trachycladines A and B and a series of analogues were examined for their cytotoxic activity against a number of cancer cell lines (glioblastoma, lung, and cervical cancer). Parent trachycladine A and two analogues (the diacetate of the 2,6-dichloropurine derivative and N-cyclopropyl trachycladine A) resulted in a significant decrease in cell viability, with the latter exhibiting a stronger effect...
February 14, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28116355/physical-determinants-of-bipolar-mitotic-spindle-assembly-and-stability-in-fission-yeast
#11
Robert Blackwell, Christopher Edelmaier, Oliver Sweezy-Schindler, Adam Lamson, Zachary R Gergely, Eileen O'Toole, Ammon Crapo, Loren E Hough, J Richard McIntosh, Matthew A Glaser, Meredith D Betterton
Mitotic spindles use an elegant bipolar architecture to segregate duplicated chromosomes with high fidelity. Bipolar spindles form from a monopolar initial condition; this is the most fundamental construction problem that the spindle must solve. Microtubules, motors, and cross-linkers are important for bipolarity, but the mechanisms necessary and sufficient for spindle assembly remain unknown. We describe a physical model that exhibits de novo bipolar spindle formation. We began with physical properties of fission-yeast spindle pole body size and microtubule number, kinesin-5 motors, kinesin-14 motors, and passive cross-linkers...
January 2017: Science Advances
https://www.readbyqxmd.com/read/28103122/ptk2-mediated-degradation-of-atg3-impedes-cancer-cells-susceptible-to-dna-damage-treatment
#12
Ke Ma, Wan Fu, Ming Tang, Chaohua Zhang, Tianyun Hou, Ran Li, Xiaopeng Lu, Yanan Wang, Jingyi Zhou, Xue Li, Luyao Zhang, Lina Wang, Ying Zhao, Wei-Guo Zhu
ATG3 (autophagy-related 3) is an E2-like enzyme essential for autophagy; however, it is unknown whether it has an autophagy-independent function. Here, we report that ATG3 is a relatively stable protein in unstressed cells, but it is degraded in response to DNA-damaging agents such as etoposide or cisplatin. With mass spectrometry and a mutagenesis assay, phosphorylation of tyrosine 203 of ATG3 was identified to be a critical modification for its degradation, which was further confirmed by manipulating ATG3(Y203E) (phosphorylation mimic) or ATG3(Y203F) (phosphorylation-incompetent) in Atg3 knockout MEFs...
March 4, 2017: Autophagy
https://www.readbyqxmd.com/read/28094252/a-signature-motif-in-lim-proteins-mediates-binding-to-checkpoint-proteins-and-increases-tumour-radiosensitivity
#13
Xiaojie Xu, Zhongyi Fan, Chaoyang Liang, Ling Li, Lili Wang, Yingchun Liang, Jun Wu, Shaohong Chang, Zhifeng Yan, Zhaohui Lv, Jing Fu, Yang Liu, Shuai Jin, Tao Wang, Tian Hong, Yishan Dong, Lihua Ding, Long Cheng, Rui Liu, Shenbo Fu, Shunchang Jiao, Qinong Ye
Tumour radiotherapy resistance involves the cell cycle pathway. CDC25 phosphatases are key cell cycle regulators. However, how CDC25 activity is precisely controlled remains largely unknown. Here, we show that LIM domain-containing proteins, such as FHL1, increase inhibitory CDC25 phosphorylation by forming a complex with CHK2 and CDC25, and sequester CDC25 in the cytoplasm by forming another complex with 14-3-3 and CDC25, resulting in increased radioresistance in cancer cells. FHL1 expression, induced by ionizing irradiation in a SP1- and MLL1-dependent manner, positively correlates with radioresistance in cancer patients...
January 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28091564/mitotic-catastrophe-is-a-putative-mechanism-underlying-the-weak-correlation-between-sensitivity-to-carbon-ions-and-cisplatin
#14
Daijiro Kobayashi, Takahiro Oike, Atsushi Shibata, Atsuko Niimi, Yoshiki Kubota, Makoto Sakai, Napapat Amornwhichet, Yuya Yoshimoto, Yoshihiko Hagiwara, Yuka Kimura, Yuka Hirota, Hiro Sato, Mayu Isono, Yukari Yoshida, Takashi Kohno, Tatsuya Ohno, Takashi Nakano
In cancer therapy today, carbon ion radiotherapy is used mainly as monotherapy, whereas cisplatin is used concomitantly with X-ray radiotherapy. The effectiveness of concomitant carbon ions and cisplatin is unclear. To obtain the information on the mechanisms potentially shared between carbon ions or X-rays and cisplatin, we assessed the correlation of sensitivity to the single treatments. In 20 human cancer cell lines, sensitivity to X-rays strongly correlated with sensitivity to cisplatin, indicating the presence of potentially shared target mechanisms...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28062704/radiosensitization-by-the-atr-inhibitor-azd6738-through-generation-of-acentric-micronuclei
#15
Magnus T Dillon, Holly E Barker, Malin Pedersen, Hind Hafsi, Shreerang A Bhide, Kate L Newbold, Christopher M Nutting, Martin McLaughlin, Kevin J Harrington
AZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found in vitro growth inhibitory activity of this ATRi in a panel of human cancer cell lines. We demonstrated radiosensitization by AZD6738 to single radiation fractions in multiple cancer cell lines independent of both p53 and BRCA2 status by the clonogenic assay. Radiosensitization by AZD6738 to clinically relevant doses of fractionated radiation was demonstrated in vitro using a 3D tumor spheroid model and, in vivo, AZD6738 radiosensitized by abrogating the radiation-induced G2 cell-cycle checkpoint and inhibiting homologous recombination...
January 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28055975/mitotic-catastrophe-and-cell-cycle-arrest-are-alternative-cell-death-pathways-executed-by-bortezomib-in-rituximab-resistant-b-cell-lymphoma-cells
#16
Juan J Gu, Gregory P Kaufman, Cory Mavis, Myron S Czuczman, Francisco J Hernandez-Ilizaliturri
The ubiqutin-proteasome system (UPS) plays a role in rituximab-chemotherapy resistance and bortezomib (BTZ) possesses caspase-dependent (i.e. Bak stabilization) and a less characterized caspase-independent mechanism-of-action(s). Here, we define BTZ-induced caspase-independent cell death pathways. A panel of rituximab-sensitive (RSCL), rituximab-resistant cell lines (RRCL) and primary tumor cells derived from lymphoma patients (N = 13) were exposed to BTZ. Changes in cell viability, cell-cycle, senescence, and mitotic index were quantified...
February 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/27987437/theranostic-approach-for-metastatic-pigmented-melanoma-using-icf15002-a-multimodal-radiotracer-for-both-pet-imaging-and-targeted-radionuclide-therapy
#17
Latifa Rbah-Vidal, Aurélien Vidal, Emilie M F Billaud, Sophie Besse, Isabelle Ranchon-Cole, Florence Mishellany, Yann Perrot, Lydia Maigne, Nicole Moins, Jean-Luc Guerquin-Kern, Françoise Degoul, Jean-Michel Chezal, Philippe Auzeloux, Elisabeth Miot-Noirault
PURPOSE: This work reports, in melanoma models, the theranostic potential of ICF15002 as a single fluorinated and iodinated melanin-targeting compound. METHODS: Studies were conducted in the murine syngeneic B16BL6 model and in the A375 and SK-MEL-3 human xenografts. ICF15002 was radiolabeled with fluorine-18 for positron emission tomography (PET) imaging and biodistribution, with iodine-125 for metabolism study, and iodine-131 for targeted radionuclide therapy (TRT)...
December 14, 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/27978798/combination-platinum-based-and-dna-damage-response-targeting-cancer-therapy-evolution-and-future-directions
#18
Spyridon P Basourakos, Likun Li, Ana M Aparicio, Paul G Corn, Jeri Kim, Timothy C Thompson
Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Alkylating factors, i.e., interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR) including DNA repair, and mainly involves the nucleotide excision repair (NER) pathway. When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis...
December 14, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27941671/non-canonical-cell-death-induced-by-p53
#19
REVIEW
Atul Ranjan, Tomoo Iwakuma
Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms of programmed cell death has gained momentum. p53 is a well characterized tumor suppressor that controls cell proliferation and apoptosis and has also been linked to non-apoptotic, non-canonical cell death mechanisms...
December 9, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27926485/axitinib-induces-senescence-associated-cell-death-and-necrosis-in-glioma-cell-lines-the-proteasome-inhibitor-bortezomib-potentiates-axitinib-induced-cytotoxicity-in-a-p21-waf-cip1-dependent-manner
#20
Maria Beatrice Morelli, Consuelo Amantini, Massimo Nabissi, Claudio Cardinali, Matteo Santoni, Giovanni Bernardini, Angela Santoni, Giorgio Santoni
Glioblastoma is associated with a poor overall survival despite new treatment advances. Antiangiogenic strategies targeting VEGF based on tyrosine kinase inhibitors (TKIs) are currently undergoing extensive research for the treatment of glioma.Herein we demonstrated that the TKI axitinib induces DNA damage response (DDR) characterized by γ-H2AX phosphorylation and Chk1 kinase activation leading to G2/M cell cycle arrest and mitotic catastrophe in U87, T98 and U251 glioma cell lines. Moreover, we found that p21(Waf1/Cip1) increased levels correlates with induction of ROS and senescence-associated cell death in U87 and T98 cell lines, which are reverted by N-acetyl cysteine pretreatment...
January 10, 2017: Oncotarget
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