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Mitotic catastrophe

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https://www.readbyqxmd.com/read/28202528/distinct-levels-of-radioresistance-in-lgr5-colonic-epithelial-stem-cells-versus-lgr5-small-intestinal-stem-cells
#1
Guoqiang Hua, Chu Wang, Yan Pan, Zhaoshi Zeng, Sang Gyu Lee, Maria Laura Martin, Adriana Haimovitz-Friedman, Zvi Fuks, Philip B Paty, Richard N Kolesnick
While 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. 1.3±0.1, respectively; p0...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28195671/trachycladines-and-analogues-synthesis-and-anti-cancer-activity-evaluation
#2
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 via 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 2,6-dichloropurine derivative and N-cyclopropyl trachycladine A) were found to result in a significant reduction of 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
#3
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
#4
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...
January 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28094252/a-signature-motif-in-lim-proteins-mediates-binding-to-checkpoint-proteins-and-increases-tumour-radiosensitivity
#5
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
#6
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
#7
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
#8
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...
December 31, 2016: 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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/27914985/combination-therapy-with-doxorubicin-loaded-galactosylated-poly-ethyleneglycol-lithocholic-acid-to-suppress-the-tumor-growth-in-an-orthotopic-mouse-model-of-liver-cancer
#13
Bijay Singh, Yoonjeong Jang, Sushila Maharjan, Hyeon-Jeong Kim, Ah Young Lee, Sanghwa Kim, Nomundelger Gankhuyag, Myeon-Sik Yang, Yun-Jaie Choi, Myung-Haing Cho, Chong-Su Cho
Despite advances in technology, neither conventional anti-cancer drugs nor current nanoparticle (NP) drugs have gained substantial success in cancer treatment. While conventional chemotherapy drugs have several limitations such as low potency, poor in vivo stability and limited bioavailability, non-specific targeting of NP drugs diminishes their potency at actual target sites. In addition, the development of drug resistance to anti-cancer drugs is another challenging problem. To overcome these limitations, we aimed to develop a polymer-drug conjugate, which functions as an active NP drug and drug carrier both, to deliver a chemotherapeutic drug for combination therapy...
February 2017: Biomaterials
https://www.readbyqxmd.com/read/27909956/docking-and-three-dimensional-quantitative-structure-activity-relationship-analyses-of-imidazole-and-thiazolidine-derivatives-as-aurora-a-kinase-inhibitors
#14
Chaeuk Im
Aurora A kinase is involved in the inactivation of apoptosis leading to ovarian, breast, colon, and pancreatic cancers. Inhibitors of Aurora A kinase promote aberrant mitosis resulting in arrest at a pseudo G1 state to induce mitotic catastrophe, ultimately leading to apoptosis. In this study, ligand-based and docking-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of imidazole and thiazolidine derivatives as potential Aurora A kinase inhibitors were performed. The results provided highly reliable and predictive 3D-QSAR comparative molecular similarity index analysis (CoMSIA) models with a cross-validated q(2) value of 0...
December 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27902925/targeted-inhibition-of-wrn-helicase-replication-stress-and-cancer
#15
REVIEW
Natalie Orlovetskie, Raphael Serruya, Ghada Abboud-Jarrous, Nayef Jarrous
WRN helicase has several roles in genome maintenance, such as replication, base excision repair, recombination, DNA damage response and transcription. These processes are often found upregulated in human cancers, many of which display increased levels of WRN. Therefore, directed inhibition of this RecQ helicase could be beneficial to selective cancer therapy. Inhibition of WRN is feasible by the use of small-molecule inhibitors or application of RNA interference and EGS/RNase P targeting systems. Remarkably, helicase depletion leads to a severe reduction in cell viability due to mitotic catastrophe, which is triggered by replication stress induced by DNA repair failure and fork progression arrest...
January 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27887793/antiproliferative-and-antimetastatic-action-of-quercetin-on-a549-non-small-cell-lung-cancer-cells-through-its-effect-on-the-cytoskeleton
#16
Anna Klimaszewska-Wiśniewska, Marta Hałas-Wiśniewska, Magdalena Izdebska, Maciej Gagat, Alina Grzanka, Dariusz Grzanka
To our knowledge, this study is the first to investigate the effect of the dietary flavonoid quercetin on the main cytoskeletal elements, namely microfilaments, microtubules and vimentin intermediate filaments, as well as cytoskeleton-driven processes in A549 non-small cell lung cancer cells. The methyl-thiazol-diphenyl-tetrazolium assay, annexin V/propidium iodide test, electron microscopic examination, cell cycle analysis based on DNA content, real-time PCR assays, in vitro scratch wound-healing assay, fluorescence staining of F-actin, β-tubulin and vimentin were performed to assess the effects of quercetin on A549 cells...
November 22, 2016: Acta Histochemica
https://www.readbyqxmd.com/read/27879648/the-role-of-deoxycytidine-kinase-dck-in-radiation-induced-cell-death
#17
Rui Zhong, Rui Xin, Zongyan Chen, Nan Liang, Yang Liu, Shumei Ma, Xiaodong Liu
Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. However, whether dCK plays a role in radiation-induced cell death is less clear. In this study, we genetically modified dCK expression by knocking down or expressing a WT (wild-type), S74A (abrogates phosphorylation) and S74E (mimics phosphorylation) of dCK...
November 21, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27878946/targeted-inhibition-of-polo-like-kinase-1-by-a-novel-small-molecule-inhibitor-induces-mitotic-catastrophe-and-apoptosis-in-human-bladder-cancer-cells
#18
Zhe Zhang, Guojun Zhang, Chuize Kong
Bladder cancer is a common cancer with particularly high recurrence after transurethral resection. Despite improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little. In this study, the anti-tumour activities of a novel Polo-like kinase 1 (PLK1) inhibitor (RO3280) was evaluated in vitro and in vivo in the bladder carcinoma cell lines 5637 and T24. MTT assays, colony-formation assays, flow cytometry, cell morphological analysis and trypan blue exclusion assays were used to examine the proliferation, cell cycle distribution and apoptosis of bladder carcinoma cells with or without RO3280 treatment...
November 23, 2016: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27863409/integrating-mechanisms-of-response-and-resistance-against-the-tubulin-binding-agent-eribulin-in-preclinical-models-of-osteosarcoma
#19
Valerie B Sampson, Nancy S Vetter, Wendong Zhang, Pratima U Patil, Robert W Mason, Erika George, Richard Gorlick, E A Kolb
Osteosarcoma is the most frequently occurring bone cancer in children and adolescents. Unfortunately, treatment failures are common. Eribulin is a synthetic microtubule inhibitor that has demonstrated activity in preclinical osteosarcoma models. The effects of eribulin were evaluated in two human osteosarcoma cell lines as well as in eribulin-sensitive and -resistant osteosarcoma xenograft tumors of the Pediatric Preclinical Testing Program (PPTP) by characterizing cell viability, microtubule destabilization, mitotic arrest and mechanism of cell death...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27861885/sensitivity-of-tp53-mutated-cancer-cells-to-the-phytoestrogen-genistein-is-associated-with-direct-inhibition-of-plk1-activity
#20
Sol-Bi Shin, Sang-Uk Woo, Young Won Chin, Young-Joo Jang, Hyungshin Yim
Polo-like kinase 1 (Plk1), a conserved Ser/Thr mitotic kinase, has been identified as a promising target for anticancer drug development because its overexpression is correlated with malignancy. Here, we found that genistein, an isoflavone, inhibits Plk1 kinase activity directly. Previously the mitotic disturbance phenomenon induced by treatment with genistein was not fully explained by its inhibitory effect on EGFR. In kinase profiling assays, it showed selectivity relative to a panel of kinases, including EGFR...
November 9, 2016: Journal of Cellular Physiology
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