Growth disadvantage associated with centrosome amplification drives population-level centriole number homeostasis

The centriole duplication cycle normally maintains number at two centrioles per G1 cell. However, some circumstances can result in an aberrant increase in centriole number. Cells with extra centrioles display extended cell cycle arrest, longer interphase durations, and death, which result in a proliferative disadvantage relative to normal cells.

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Antiproliferative and Apoptosis-Inducing Activities of Benchalokawichian Remedy Against Doxorubicin-Sensitive and -Resistant Erythromyelogenous Leukemic Cells

Chiang Mai University Journal of Natural Sciences ◽

10.12982/cmujns.2021.056 ◽

2021 ◽

Vol 20 (3) ◽

Author(s):

Wipob Suttana ◽

Chatubhong Singharachai ◽

Rawiwan Charoensup ◽

Narawadee Rujanapun ◽

Chutima Suya

Keyword(s):

Cell Cycle ◽

Multidrug Resistance ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

K562 Cells ◽

Leukemic Cells ◽

Drug Resistant ◽

Normal Cells ◽

Root Extracts ◽

Cycle Arrest

Chemotherapy can cause multidrug resistance in cancer cells and is cytotoxic to normal cells. Discovering natural bioactive compounds that are not cytotoxic to normal cells but inhibit proliferation and induce apoptosis in drug- sensitive and drug-resistant cancer cells could overcome these drawbacks of chemotherapy. This study investigated the antiproliferative effects of crude extracts of Benchalokawichian (BLW) remedy and its herbal components against drug-sensitive and drug-resistant cancer cells, cytotoxicity of the extracts toward normal cells, and their ability to induce apoptosis and cell cycle arrest in drug-sensitive and drug-resistant cancer cells. The extracts exhibited antiproliferative activity against doxorubicin-sensitive and doxorubicin-resistant erythromyelogenous leukemic cells (K562 and K562/adr). Tiliacora triandra root, BLW, and Harrisonia perforata root extracts displayed an IC50 of 77.00 ± 1.30, 79.33 ± 1.33, and 87.67 ± 0.67 µg/mL, respectively, against K562 cells. In contrast, Clerodendrum petasites, T. triandra, and H. perforata root extracts displayed the lowest IC50 against K562/adr cells (68.89 ± 0.75, 78.33 ± 0.69, and 86.78 ± 1.92 µg/mL, respectively). The resistance factor of the extracts was lower than that of doxorubicin, indicating that the extracts could overcome the multidrug resistance of cancer cells. Importantly, the extracts were negligibly cytotoxic to peripheral mononuclear cells, indicating minimal adverse effects in normal cells. In addition, these extracts induced apoptosis of K562 and K562/adr cells and caused cell cycle arrest at the G0/G1 phase in K562 cells. Keywords: Antiproliferative, Apoptosis, Benchalokawichian, Cell cycle, Multidrug resistance

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Antimalarial agent artesunate induces G0/G1 cell cycle arrest and apoptosis via increasing intracellular ROS levels in normal liver cells

Human & Experimental Toxicology ◽

10.1177/0960327120937331 ◽

2020 ◽

Vol 39 (12) ◽

pp. 1681-1689

Author(s):

S Yin ◽

H Yang ◽

X Zhao ◽

S Wei ◽

Y Tao ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Arrest ◽

Normal Liver ◽

Liver Cells ◽

Phase Cell ◽

Normal Cells ◽

Cycle Arrest ◽

Intracellular Ros ◽

G1 Cell Cycle Arrest

Artesunate (ARS) has been shown to be highly effective against chloroquine-resistant malaria. In vitro studies reported that ARS has anticancer effects; however, its detrimental action on cancer cells may also play a role in its toxicity toward normal cells and its potential toxicity has not been sufficiently researched. In this study, we investigated the possible cytotoxic effects using normal BRL-3A and AML12 liver cells. The results showed that ARS dose-dependently inhibited cell proliferation and arrested the G0/G1 phase cell cycle in both BRL-3A and AML12 liver cells. Western blotting demonstrated that ARS induced a significant downregulation of cyclin-dependent kinase-2 (CDK2), CDK4, cyclin D1, and cyclin E1 in various levels and then caused apoptosis when the Bcl-2/Bax ratio decreased. Conversely, the levels of intracellular reactive oxygen species (ROS) were increased. The ROS scavenger N-acetylcysteine can significantly inhibit cell cycle arrest and apoptosis induced by ARS. Thus, the data confirmed that ARS exposure impairs normal liver cell proliferation by inducing G0/G1 cell cycle arrest and apoptosis, and this detrimental action may be associated with intracellular ROS accumulation. Collectively, the possible side effects of ARS on healthy normal cells cannot be neglected when developing therapies.

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p53 protects against genome instability following centriole duplication failure

The Journal of Cell Biology ◽

10.1083/jcb.201502089 ◽

2015 ◽

Vol 210 (1) ◽

pp. 63-77 ◽

Cited By ~ 91

Author(s):

Bramwell G. Lambrus ◽

Yumi Uetake ◽

Kevin M. Clutario ◽

Vikas Daggubati ◽

Michael Snyder ◽

...

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Cell Cycle Arrest ◽

Gene Targeting ◽

Chromosome Segregation ◽

De Novo ◽

Genome Instability ◽

Centriole Duplication ◽

Cycle Arrest ◽

Surveillance Mechanism

Centriole function has been difficult to study because of a lack of specific tools that allow persistent and reversible centriole depletion. Here we combined gene targeting with an auxin-inducible degradation system to achieve rapid, titratable, and reversible control of Polo-like kinase 4 (Plk4), a master regulator of centriole biogenesis. Depletion of Plk4 led to a failure of centriole duplication that produced an irreversible cell cycle arrest within a few divisions. This arrest was not a result of a prolonged mitosis, chromosome segregation errors, or cytokinesis failure. Depleting p53 allowed cells that fail centriole duplication to proliferate indefinitely. Washout of auxin and restoration of endogenous Plk4 levels in cells that lack centrioles led to the penetrant formation of de novo centrioles that gained the ability to organize microtubules and duplicate. In summary, we uncover a p53-dependent surveillance mechanism that protects against genome instability by preventing cell growth after centriole duplication failure.

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Inhibition of p53 improves CRISPR/Cas - mediated precision genome editing

10.1101/180943 ◽

2017 ◽

Cited By ~ 2

Author(s):

Emma Haapaniemi ◽

Sandeep Botla ◽

Jenna Persson ◽

Bernhard Schmierer ◽

Jussi Taipale

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Homologous Recombination ◽

Cell Cycle Arrest ◽

Genome Editing ◽

Dna Damage Response ◽

Normal Cells ◽

Cycle Arrest ◽

Damage Response

AbstractWe report here that genome editing by CRISPR/Cas9 induces a p53-mediated DNA damage response and cell cycle arrest. Transient inhibition of p53 prevents this response, and increases the rate of homologous recombination more than five-fold. This provides a way to improve precision genome editing of normal cells, but warrants caution in using CRISPR for human therapies until the mechanism of the activation of p53 is elucidated.

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PO-1932 Cell cycle arrest induced by AsiDNA in normal cells: a possible mechanism for radioprotection?

Radiotherapy and Oncology ◽

10.1016/s0167-8140(21)08383-3 ◽

2021 ◽

Vol 161 ◽

pp. S1646

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Normal Cells ◽

Cycle Arrest

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Synthesis, characterization and antitumor activity of novel tetrapodal 1,4-dihydropyridines: p53 induction, cell cycle arrest and low damage effect on normal cells induced by genotoxic factor H2O2

RSC Advances ◽

10.1039/c6ra04974e ◽

2016 ◽

Vol 6 (47) ◽

pp. 40900-40910 ◽

Cited By ~ 32

Author(s):

Magda F. Mohamed ◽

Ahmed F. Darweesh ◽

Ahmed H. M. Elwahy ◽

Ismail A. Abdelhamid

Keyword(s):

Cell Cycle ◽

Antitumor Activity ◽

Cell Cycle Arrest ◽

Damage Effect ◽

Antitumor Activities ◽

Normal Cells ◽

Cycle Arrest ◽

Acid Catalyzed

Synthesis of novel tetrakis(2,6-dimethyl-4-phenyl-1,4-dihydropyridinyl)methanes5a–dby acid-catalyzed condensation of the tetrakis-aldehydes6a–dwith eight equivalents of 3-aminobut-2-enenitrile2is reported. Antitumor activities of compounds5a–dwere also investigated.

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A New Perspective for Osteosarcoma Therapy: Proteasome Inhibition by MLN9708/2238 Successfully Induces Apoptosis and Cell Cycle Arrest and Attenuates the Invasion Ability of Osteosarcoma Cells in Vitro

Cellular Physiology and Biochemistry ◽

10.1159/000456598 ◽

2017 ◽

Vol 41 (2) ◽

pp. 451-465 ◽

Cited By ~ 5

Author(s):

Renhao Liu ◽

Chunjiang Fu ◽

Jiabing Sun ◽

Xvming Wang ◽

Shuo Geng ◽

...

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Cell Cycle Arrest ◽

Proteasome Inhibitor ◽

Proteasome Inhibition ◽

Mitochondrial Outer Membrane ◽

Normal Cells ◽

Mitochondrial Outer Membrane Permeabilization ◽

Cycle Arrest

Background: The proteasome exists in all eukaryotic cells and provides the main route of intracellular proteins degradation involved in cell growth and apoptosis. Proteasome inhibition could block protein degradation pathways and disturb regulatory networks, possibly leading to profound effects on cell growth, particularly in cancer cells. A proteasome inhibitor with an appropriate toxicity index for malignant cells rather than normal cells would be an attractive anticancer therapy. Methods: The human osteosarcoma (OS) cell lines MG-63 and Saos-2 and normal osteoblast cells were used to study the antitumour activity of the proteasome inhibitor MLN9708/2238. Results: MLN2238 inhibited cell growth, induced cell cycle arrest and apoptosis, and attenuated the invasion abilities of MG-63 and Saos-2 cells, with little cytotoxicity to normal cells. In addition, MLN2238 promoted antitumour mechanisms including the accumulation of E2F1, P53, P21 and other negative G2/M checkpoint proteins; up-regulated the relative expression ratio of BAX/BCL-2, APAF-1 and pro-apoptotic proteins of the BCL-2 family; triggered mitochondrial outer membrane permeabilization (MOMP); down-regulated BCL-2 and XIAP; activated caspase3/8/9; and suppressed MMP2/9 expression and secretion levels. Conclusions: The proteasome may be a novel biochemical target for OS treatment in vitro. Our study provides a promising mechanistic framework for MLN9708/2238 in OS treatment, supporting its clinical development.

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Inhibition of centriole duplication by centrobin depletion leads to p38–p53 mediated cell-cycle arrest

Cellular Signalling ◽

10.1016/j.cellsig.2010.01.009 ◽

2010 ◽

Vol 22 (5) ◽

pp. 857-864 ◽

Cited By ~ 7

Author(s):

Libing Song ◽

Ting Dai ◽

Huaping Xiong ◽

Chuyong Lin ◽

Huanxin Lin ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Centriole Duplication ◽

Cycle Arrest

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Computational Model of G2-M DNA Damage Checkpoint Regulation in Normal and p53-null Cancer Cells

10.1101/2020.06.17.158246 ◽

2020 ◽

Author(s):

Yongwoon Jung ◽

Pavel Kraikivski

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Computational Model ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Cell Cycle Progression ◽

Dna Damage Checkpoint ◽

Cycle Progression ◽

Normal Cells ◽

Cycle Arrest

AbstractCancer and normal cells can respond differently to the same stressful conditions. Their dynamic responses under normal and stressful conditions are governed by complex molecular regulatory networks. We developed a computational model of G2-M DNA damage checkpoint regulation to study normal and cancer cell cycle progression under normal and stressful conditions. Our model is successful in explaining cancer cell cycle arrest in conditions when some cell cycle and DNA damage checkpoint regulators are inhibited, whereas the same conditions only delay entry into mitosis in normal cells. We use the model to explain known phenotypes of gene deletion mutants and predict phenotypes of yet uncharacterized mutants in normal and cancer cells. We also use sensitive analyses to identify the ranges of model parameter values that lead to the cell cycle arrest in cancer cells. Our results can be used to predict the effect of a potential treatment on cell cycle progression of normal and cancer cells.

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