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Mitotic catastrophe

Claire Levrier, Martin C Sadowski, Anja Rockstroh, Brian Gabrielli, Maria Kavallaris, Melanie Lehman, Rohan A Davis, Colleen C Nelson
The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6α-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC-3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis...
October 19, 2016: Molecular Cancer Therapeutics
Melania Ester Mercado-Pimentel, Craig Miller, Daniela N Rolph, Edrick F Villalobos, Allison M Dunn, Prithvi M Mohan, Suzu Igarashi, Xiangdang Liu, Macken Yrun-Duffy, Neal K Patel, Cecilia M Read, Ross H Francis, Adelina Isabella Lane, Swaroop Murugesh, Abraham Jacob
HYPOTHESIS: p21-activated kinase (PAK) regulates signaling pathways that promote cell survival and proliferation; therefore, pharmacological inhibition of PAK will induce cell death in vestibular schwannomas (VS) and meningiomas. BACKGROUND: All VS and many meningiomas result from loss of the neurofibromatosis type 2 (NF2) gene product merlin, with ensuing PAK hyperactivation and increased cell proliferation/survival. METHODS: The novel small molecule PAK inhibitors PI-8 and PI-15-tested in schwannoma and meningioma cells-perturb molecular signaling and induce cell death...
October 12, 2016: Otology & Neurotology
Gianandrea Traversi, Mario Fiore, Zulema Percario, Francesca Degrassi, Renata Cozzi
Natural compounds are extensively studied for their potential use in traditional and non-traditional medicine. Several natural and synthetic Resveratrol analogues have shown interesting biological activities in the field of cancer chemoprevention. In the present study, we have focused on the ability of Resveratrol and two methoxylated derivatives (Trimethoxystilbene and Pterostilbene) to inhibit human cancer cell growth particularly analyzing their ability to interfere with tubulin dynamics at mitosis. We show that Trimethoxystilbene, differently from Resveratrol and Pterostilbene, alters microtubule polymerization dynamics in HeLa cells specifically inducing multipolar spindles and mitotic arrest coupled to a reduction of cell growth and an increase in apoptotic death by mitotic catastrophe...
October 14, 2016: Molecular Carcinogenesis
Seongyeong Kim, Ahrum Min, Kyung-Hun Lee, Yaewon Yang, Tae-Yong Kim, Jee Min Lim, So Jung Park, Hyun-Jin Nam, Jung Eun Kim, Sang-Hyun Song, Sae-Won Han, Do-Youn Oh, Jee Hyun Kim, Tae-You Kim, David Hangauer, Johnson Yiu-Nam Lau, Kyongok Im, Dong Soon Lee, Yung-Jue Bang, Seock-Ah Im
Purpose: KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo. Materials and Methods: The anti-tumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay...
October 6, 2016: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Shuai Hou, Na Li, Qian Zhang, Hui Li, Xinyue Wei, Tian Hao, Yue Li, Sikandar Azam, Caigang Liu, Wei Cheng, Bilian Jin, Quentin Liu, Man Li, Haixin Lei
Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2) is a multi-functional protein that plays critical role in processes including transcription, transcription-coupled DNA repair, pre-mRNA splicing, homologous recombination and mRNA export. Microarray analysis on gene expression in XAB2 knockdown cells reveals that many genes with significant change in expression function in mitotic cell cycle regulation. Fluorescence-activated cell scanner analysis confirmed XAB2 depletion led to cell arrest in G2/M phase, mostly at prophase or prometaphase...
October 13, 2016: Cell Death & Disease
Yoo Hong Min, Wootae Kim, Ja-Eun Kim
Mitotic progression is crucial for the maintenance of chromosomal stability. A proper progression is ensured by the activities of multiple kinases. One of these enzymes, the serine/threonine kinase Aurora A, is required for proper mitosis through the regulation of centrosome and spindle assembly. In this study, we functionally characterized a newly developed Aurora kinase A inhibitor, TC-A2317. In human lung cancer cells, TC-A2317 slowed proliferation by causing aberrant formation of centrosome and microtubule spindles and prolonging the duration of mitosis...
October 4, 2016: Oncotarget
Yijun Zhang, Youguang Luo, Rui Lyu, Jie Chen, Ruming Liu, Dengwen Li, Min Liu, Jun Zhou
Cell migration, a complex process critical for tumor progression and metastasis, requires a dynamic crosstalk between microtubules (MTs) and focal adhesions (FAs). However, the molecular mechanisms underlying this event remain elusive. Herein we identify the proto-oncogenic protein Src as an important player in the regulation of the MT-FA crosstalk. Src interacts with and phosphorylates end-binding protein 1 (EB1), a member of MT plus end-tracking proteins (+TIPs), both in cells and in vitro. Systematic mutagenesis reveals that tyrosine-247 (Y247) is the primary residue of EB1 phosphorylated by Src...
2016: Theranostics
Martin Převorovský, Martina Oravcová, Róbert Zach, Anna Jordáková, Jürg Bähler, František Půta, Petr Folk
For every eukaryotic cell to grow and divide, intricately coordinated action of numerous proteins is required to ensure proper cell-cycle progression. The fission yeast Schizosaccharomyces pombe has been instrumental in elucidating the fundamental principles of cell-cycle control. Mutations in S. pombe 'cut' (cell untimely torn) genes cause failed coordination between cell and nuclear division, resulting in catastrophic mitosis. Deletion of cbf11, a fission yeast CSL transcription factor gene, triggers a 'cut' phenotype, but the precise role of Cbf11 in promoting mitotic fidelity is not known...
September 29, 2016: Cell Cycle
Karol Jaroch, Maciej Karolak, Przemysław Górski, Alina Jaroch, Adrian Krajewski, Aleksandra Ilnicka, Anna Sloderbach, Tomasz Stefański, Stanisław Sobiak
For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways...
August 24, 2016: Pharmacological Reports: PR
Younghyun Lee, Huizi Keiko Li, Aya Masaoka, Shigeaki Sunada, Hirokazu Hirakawa, Akira Fujimori, Jac A Nickoloff, Ryuichi Okayasu
BACKGROUND AND PURPOSE: PU-H71 is a purine-scaffold Hsp90 inhibitor developed to overcome limitations of conventional Hsp90 inhibitors. This study was designed to investigate the combined effect of PU-H71 and heavy ion irradiation on human tumor and normal cells. MATERIALS AND METHODS: The effects of PU-H71 were determined by monitoring cell survival by colony formation, and DNA double-strand break (DSB) repair by γ-H2AX foci and immuno-blotting DSB repair proteins...
September 22, 2016: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Amal Fawzy, Karima M Sweify, Hany M El-Fayoumy, Nagwa Nofal
BACKGROUND: Prostate cancer (PC) is the most common cancer affecting men, it accounts for 29% of all male cancer and 11% of all male cancer related death. DNA is normally released from an apoptotic source which generates small fragments of cell-free DNA, whereas cancer patients have cell-free circulating DNA that originated from necrosis, autophagy, or mitotic catastrophe, which produce large fragments. AIM OF WORK: Differentiate the cell free DNA levels (cfDNA) and its integrity in prostate cancer patients and control group composed of benign prostate hyperplasia (BPH) and healthy persons...
September 12, 2016: Journal of the Egyptian National Cancer Institute
Ritam Chatterjee, Sukalpa Chattopadhyay, Sujata Law
Aplastic anemia, the paradigm of bone marrow failure, is characterized by pancytopenic peripheral blood and hypoplastic bone marrow. Among various etiologies, inappropriate use of DNA alkylating drugs like cyclophosphamide and busulfan often causes the manifestation of the dreadful disease. Cell cycle impairment in marrow hematopoietic stem/progenitor compartment together with cellular apoptosis has been recognized as culpable factors behind aplastic pathophysiologies. However, the intricate molecular mechanisms remain unrevealed till date...
November 2016: Molecular and Cellular Biochemistry
Stephanie A Yazinski, Lee Zou
The ATR (ATM and rad3-related) pathway is crucial for proliferation, responding to DNA replication stress and DNA damage. This critical signaling pathway is carefully orchestrated through a multistep process requiring initial priming of ATR prior to damage, recruitment of ATR to DNA damage lesions, activation of ATR signaling, and, finally, modulation of ATR activity through a variety of post-translational modifications. Following activation, ATR functions in several vital cellular processes, including suppression of replication origin firing, promotion of deoxynucleotide synthesis and replication fork restart, prevention of double-stranded DNA break formation, and avoidance of replication catastrophe and mitotic catastrophe...
September 8, 2016: Annual Review of Genetics
Shruti Lal, Mahsa Zarei, Saswati N Chand, Emanuela Dylgjeri, Nicole C Mambelli-Lisboa, Michael J Pishvaian, Charles J Yeo, Jordan M Winter, Jonathan R Brody
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease, in part, because of the lack of effective targeted therapeutic options. MK-1775 (also known as AZD1775), a mitotic inhibitor, has been demonstrated to enhance the anti-tumor effects of DNA damaging agents such as gemcitabine. We evaluated the efficacy of MK-1775 alone or in combination with DNA damaging agents (MMC or oxaliplatin) in PDA cell lines that are either DNA repair proficient (DDR-P) or deficient (DDR-D). PDA cell lines PL11, Hs 766T and Capan-1 harboring naturally selected mutations in DNA repair genes FANCC, FANCG and BRCA2 respectively, were less sensitive to MK-1775 as compared to two out of four representative DDR-P (MIA PaCa2 and PANC-1) cell lines...
2016: Scientific Reports
Carmen Dorneburg, Annika V Goß, Matthias Fischer, Frederik Roels, Thomas F E Barth, Frank Berthold, Roland Kappler, Franz Oswald, Jens T Siveke, Jan J Molenaar, Klaus-Michael Debatin, Christian Beltinger
As high-risk neuroblastoma (NB) has a poor prognosis, new therapeutic modalities are needed. We therefore investigated the susceptibility of NB cells to γ-secretase inhibitor I (GSI-I). NOTCH signaling activity, the cellular effects of GSI-I and its mechanisms of cytotoxicity were evaluated in NB cells in vitro and in vivo. The results show that NOTCH signaling is relevant for human NB cells. Of the GSIs screened in vitro GSI-I was the most effective inhibitor of NB cells. Both MYCN-amplified and non-amplified NB cells were susceptible to GSI-I...
August 30, 2016: Oncotarget
Jessica Günzle, Nadja Osterberg, Joseph E Saavedra, Astrid Weyerbrock
The nitric oxide (NO) donor JS-K is specifically activated by glutathione S-transferases (GSTs) in GST-overexpressing cells. We have shown the induction of cell death in glioblastoma multiforme (GBM) cells at high JS-K doses but the mechanism remains unclear. The aim of this study was to determine whether NO-induced cell death is triggered by induction of apoptotic or necrotic pathways. For the first time, we demonstrate that NO induces cell death via mitotic catastrophe (MC) with non-apoptotic mechanisms in GBM cells...
2016: Cell Death & Disease
Aneta Koceva-Chyła, Karolina Matczak, Msc Paweł Hikisz, Msc Kamil Durka, Msc Krzysztof Kochel, Georg Süss-Fink, Julien Furrer, Konrad Kowalski
The in vitro anticancer activity of the dinuclear trithiolato-bridged arene ruthenium complex diruthenium-1 (DiRu-1) was evaluated against a panel of human cancer cell lines used as in vitro models for hepatocellular carcinoma (HepG2 cells), estrogen-responsive breast adenocarcinoma (MCF-7 cells), and triple-negative breast adenocarcinoma (MDA-MB-231 cells). DiRu-1 is highly cytotoxic to these cell lines, demonstrating half-maximal inhibitory concentrations (IC50 ) in the low-nanomolar range (77±1.4 to 268...
October 6, 2016: ChemMedChem
J-Y Chien, S-D Tsen, C-C Chien, H-W Liu, C-Y Tung, C-H Lin
α-Tubulin acetyltransferase 1 (αTAT1) controls reversible acetylation on Lys40 of α-tubulin and modulates multiple cellular functions. αTAT1 depletion induced morphological defects of touch receptor neurons in Caenorhabditis elegans and impaired cell adhesion and contact inhibition in mouse embryonic fibroblasts, however, no morphological or proliferation defects in human RPE-hTERT cells were found after αTAT1-specific siRNA treatment. Here, we compared the effect of three αTAT1-specific shRNAs on proliferation and morphology in two human cell lines, HeLa and A549...
2016: Cell Death Discovery
Alexey V Danilov, Shanhu Hu, Bernardo Orr, Kristina Godek, Lisa Maria Mustachio, David Sekula, Xi Liu, Masanori Kawakami, Faye M Johnson, Duane A Compton, Sarah J Freemantle, Ethan Dmitrovsky
Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase catastrophe in response to inhibition of cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced tumor cell growth. In this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on lung cancer cells were investigated...
August 22, 2016: Molecular Cancer Therapeutics
Zhengzhe An, Jae-Ran Yu, Woo-Yoon Park
T0070907 (T007), a PPARγ inhibitor, can reduce α and β tubulin proteins in some cancer cell lines. Thus, T007 has been suggested as an antimicrotubule drug. We previously reported that T007 increased radiosensitivity by inducing mitotic catastrophe in cervical cancer cells. In this study, we investigated the underlying mechanisms of the T007-mediated increase in radiosensitivity. T007 pre-treatment attenuated RAD51 protein levels and ionising radiation (IR)-induced nuclear foci formation, resulting in more frequent centrosome amplification and multipolar mitotic spindle formation in cervical cancer cells...
December 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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