Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

AbstractIn this study, we examined the fluctuation in radioresponse of HeLa cells during the cell cycle. For this purpose, we used HeLa cells expressing two types of fluorescent ubiquitination-based cell cycle indicators (Fucci), HeLa-Fucci (CA)2 and HeLa-Fucci (SA), and combined this approach with the micronucleus (MN) assay to assess radioresponse. The Fucci system distinguishes cell cycle phases based on the colour of fluorescence and cell morphology under live conditions. Time-lapse imaging allowed us to further identify sub-positions within the G1 and S phases at the time of irradiation by two independent means, and to quantitate the number of MNs by following each cell through M phase until the next G1 phase. Notably, we found that radioresponse was low in late G1 phase, but rapidly increased in early S phase. It then decreased until late S phase and increased in G2 phase. For the first time, we demonstrated the unique fluctuation of radioresponse by the MN assay during the cell cycle in HeLa cells. We discuss the difference between previous clonogenic experiments using M phase-synchronised cell populations and ours, as well as the clinical implications of the present findings.

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Estrogen Receptor Beta Displays Cell Cycle-Dependent Expression and Regulates the G1 Phase through a Non-Genomic Mechanism in Prostate Carcinoma Cells

Analytical Cellular Pathology ◽

10.1155/2008/129726 ◽

2008 ◽

Vol 30 (4) ◽

pp. 349-365 ◽

Cited By ~ 1

Author(s):

Antoni Hurtado ◽

Tomàs Pinós ◽

Anna Barbosa-Desongles ◽

Sandra López-Avilés ◽

Jordi Barquinero ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Estrogen Receptor ◽

Estrogen Receptor Beta ◽

Mechanisms Of Action ◽

S Phase ◽

G1 Phase ◽

Over Expression ◽

M Phase ◽

Receptor Beta

Background: It is well known that estrogens regulate cell cycle progression, but the specific contributions and mechanisms of action of the estrogen receptor beta (ERβ) remain elusive.Methods: We have analyzed the levels of ERβ1 and ERβ2 throughout the cell cycle, as well as the mechanisms of action and the consequences of the over-expression of ERβ1 in the human prostate cancer LNCaP cell line.Results: Both ERβ1 mRNA and protein expression increased from the G1 to the S phase and decreased before entering the G2/M phase, whereas ERβ2 levels decreased during the S phase and increased in the G2/M phase. ERβ1 protein was detected in both the nuclear and non-nuclear fractions, and ERβ2 was found exclusively in the nucleus. Regarding the mechanisms of action, endogenous ERβ was able to activate transcription via ERE during the S phase in a ligand-dependent manner, whereas no changes in AP1 and NFκB transactivation were observed after exposure to estradiol or the specific inhibitor ICI 182,780. Over-expression of either wild type ERβ1 or ERβ1 mutated in the DNA-binding domain caused an arrest in early G1. This arrest was accompanied by the interaction of over-expressed ERβ1 with c-Jun N-terminal protein kinase 1 (JNK1) and a decrease in c-Jun phosphorylation and cyclin D1 expression. The administration of ICI impeded the JNK1–ERβ1 interaction, increased c-Jun phosphorylation and cyclin D1 expression and allowed the cells to progress to late G1, where they became arrested.Conclusions: Our results demonstrate that, in LNCaP prostate cancer cells, both ERβ isoforms are differentially expressed during the cell cycle and that ERβ regulates the G1 phase by a non-genomic mechanism.

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CD4+ Lymphocytes in Asymptomatic HTLV-1 Carriers Present Cell Cycle Arrest in G0/G1-Phase

Blood ◽

10.1182/blood.v124.21.5377.5377 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5377-5377 ◽

Cited By ~ 1

Author(s):

Mari Cleia Martins Rodrigues Ferreira ◽

Renata Kikuchi Foltran ◽

Rodrigo Santucci ◽

Luis Alberto de Padua Covas Lage ◽

Debora Levy ◽

...

Keyword(s):

Cell Cycle ◽

S Phase ◽

High Rate ◽

G1 Phase ◽

Control Group ◽

Dna Index ◽

Asymptomatic Carriers ◽

M Phase ◽

And Control ◽

Cd4 Lymphocytes

Abstract Introduction: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive and incurable disease caused by human T-lymphotropic virus 1 (HTLV-1) that infects CD4+ and CD8+ lymphocytes, but most commonly the malignant cell present a CD4+ phenotype. However, clonal expansion and cell cycle abnormalities have been demonstrated in CD4+ and in CD8+ lymphocytes of HTLV-1 carriers. Objectives: This study compared DNA content and G0/G1, G2/M and “S”-phases of CD4+ and CD8+ lymphocytes among asymptomatic HTLV-1 carriers, ATLL and health subjects. Methods: Werestudied 38 HTLV-1 carriers, 20 ATLL and 35 health subjects pared by sex and age at the Hematology Department of the Faculty of Medicine, University of São Paulo. Peripheral blood mononuclear cells (PBMCs) were isolated on Ficoll-Paque® and lymphocytes subtypes were obtained by positive selection in a magnetic column. Cell-cycle distribution and DNA index (DI) was assessed by flow cytometry after propidium iodide staining. Results: In ATLL, themedian age was 53.5 years (24 to 72) and 50% were female, in HTLV-1 carriers was 55.5 years (33 to 80) with 63.2% of female and in control group was 50 years (24 to 80) with 54.3% of female. In the CD4+ lymphocyte a % of cells in G0/G1 (98.32%) in HTLV-1 carriers was higher than in control group (97.14%) (p=0.041) and in ATLL (97.25%) (p=0.023). S-phase was not statistically different in asymptomatic carriers (0.34%) and control group (0.63%) (p=0.073), but was higher in ATLL (1.80%) than in asymptomatic carriers (0.34%) (p<0.001) and in control group (0.63%) (p=0.02). G2/M-phase was not significantly different among all groups (p=0.960) (Table 1). The CD4+ lymphocytes were aneuploidy in 39.5% (18.4% DI > 1.05 and 21.5% < 0.95) of asymptomatic carriers and in 26.7% (20% > 1.05 and 6.7% < 0.95) of ATLL patients (p=0.557). All control groups were diploid. Table 1.Comparison of the cell cycle by flow cytometry of T lymphocytes CD4+CD4+ cellsAsymptomatic carriersATLLControl groupp-ValueG0/G1mean(dp)97.78 (2.182)95.69 (3.557)96.55 (2.964)0.0351º; median;3ºq97.03;98.32;99.6491.40;97.25;98.3295.01;97.14;98.64G2/Mmean(dp)1.55(1.848)1.91(2.798)2.03(2.902)0.961º; median;3ºq0.00;0.88;2.670.12;0.99;1.990.00;0.56;2.97S-phasemean(dp)0.68(1.207)2.80(3.372)1.43(1.780)0.0031º; median;3ºq0.00;0.34;0.650.65;1.80;3.510.04;0.63;2.55 In CD8+ there was no found significantly difference in whole groups for G0/G1-phase (p=0.138) and G2/M-phase (p=0.374). ATLL presented higher S-phase (median 1.54%) than asymptomatic carriers (median 0.45%) (p=0.003) and control group. S-phase in asymptomatic carriers was not significantly different in comparison to control group (p=0.712). CD8+ were aneuploidy in 23.7% (5.3% DI > 1.05 and 18.4% < 0.95) of asymptomatic carriers and in 21% (10.5% > 1.05 and 10.5% < 0.95) of ATLL (p=0.603). In ATLL the median of DI was 1.01 (1.0; 1.05) in CD4+ and higher than in CD8+ median 0.99 (0.98; 1.0) (p=0.007). Aneuploidia was seen in 47.7% of ATLL, 26,7% (20% DI > 1.05 and 6,7% < 0.95) in CD4+ and 21,0% in CD8+ (10,5% > 1.05 and10,5% < 0.95) (p=0.625). Figure 1: Dna index of CD4+ and CD8+. Aneuploidia was found in HTLV I carriers in both CD4+ and CD8+. Figure 1:. Dna index of CD4+ and CD8+. Aneuploidia was found in HTLV I carriers in both CD4+ and CD8+. Figure 2. Comparison of DI between CD4+ and CD8+ of asymptomatic carriers and ATLL Figure 2. Comparison of DI between CD4+ and CD8+ of asymptomatic carriers and ATLL Figure 3 Figure 3. Conclusion: We demonstrated for the first time “in vivo” that asymptomatic HTLV-1 carriers display cell cycle arrest in G0/G1-phase in CD4+ lymphocytes and high rate of aneuploidia in both CD4+ and CD8+. ATLL showed high rate of hiperdiploidia in CD4+ and hipodiploidia in CD8+ and high rate of S-phase in CD4+. Genetic instability and proliferative disturbs are a hallmark not only in ATLL but also in HTLV-1 carriers and in both CD4+ and CD8+ lymphocytes. Disclosures No relevant conflicts of interest to declare.

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Faculty Opinions recommendation of Coordination of mitochondrial bioenergetics with G1 phase cell cycle progression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1116434.572453 ◽

2008 ◽

Author(s):

Robert Abraham

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Phase Cell ◽

G1 Phase ◽

Mitochondrial Bioenergetics ◽

Cycle Progression

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The Antiproliferative Activity of Oxypeucedanin via Induction of G2/M Phase Cell Cycle Arrest and p53-Dependent MDM2/p21 Expression in Human Hepatoma Cells

Molecules ◽

10.3390/molecules25030501 ◽

2020 ◽

Vol 25 (3) ◽

pp. 501

Author(s):

So Hyun Park ◽

Ji-Young Hong ◽

Hyen Joo Park ◽

Sang Kook Lee

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Antiproliferative Activity ◽

Hepatoma Cells ◽

Phase Cell ◽

Human Hepatoma Cells ◽

Cycle Arrest ◽

Growth Inhibitory Activity ◽

M Phase

Oxypeucedanin (OPD), a furocoumarin compound from Angelica dahurica (Umbelliferae), exhibits potential antiproliferative activities in human cancer cells. However, the underlying molecular mechanisms of OPD as an anticancer agent in human hepatocellular cancer cells have not been fully elucidated. Therefore, the present study investigated the antiproliferative effect of OPD in SK-Hep-1 human hepatoma cells. OPD effectively inhibited the growth of SK-Hep-1 cells. Flow cytometric analysis revealed that OPD was able to induce G2/M phase cell cycle arrest in cells. The G2/M phase cell cycle arrest by OPD was associated with the downregulation of the checkpoint proteins cyclin B1, cyclin E, cdc2, and cdc25c, and the up-regulation of p-chk1 (Ser345) expression. The growth-inhibitory activity of OPD against hepatoma cells was found to be p53-dependent. The p53-expressing cells (SK-Hep-1 and HepG2) were sensitive, but p53-null cells (Hep3B) were insensitive to the antiproliferative activity of OPD. OPD also activated the expression of p53, and thus leading to the induction of MDM2 and p21, which indicates that the antiproliferative activity of OPD is in part correlated with the modulation of p53 in cancer cells. In addition, the combination of OPD with gemcitabine showed synergistic growth-inhibitory activity in SK-Hep-1 cells. These findings suggest that the anti-proliferative activity of OPD may be highly associated with the induction of G2/M phase cell cycle arrest and upregulation of the p53/MDM2/p21 axis in SK-HEP-1 hepatoma cells.

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Involvement of the p38 MAPK signaling pathway in S-phase cell-cycle arrest induced by Furazolidone in human hepatoma G2 cells

Journal of Applied Toxicology ◽

10.1002/jat.2829 ◽

2012 ◽

Vol 33 (12) ◽

pp. 1500-1505 ◽

Cited By ~ 6

Author(s):

Yu Sun ◽

Shusheng Tang ◽

Xi Jin ◽

Chaoming Zhang ◽

Wenxia Zhao ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Signaling Pathway ◽

P38 Mapk ◽

Mapk Signaling ◽

S Phase ◽

Mapk Signaling Pathway ◽

Phase Cell ◽

Human Hepatoma ◽

Cycle Arrest

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Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells

Biomolecules ◽

10.3390/biom9080302 ◽

2019 ◽

Vol 9 (8) ◽

pp. 302 ◽

Cited By ~ 10

Author(s):

Xin Zhang ◽

Yao Qin ◽

Zhaohai Pan ◽

Minjing Li ◽

Xiaona Liu ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Cycle ◽

Protein Expression ◽

Cell Cycle Arrest ◽

Phase Cell ◽

G1 Phase ◽

Therapeutic Effects ◽

Human Gastric Cancer ◽

Expression Levels ◽

Cycle Arrest

The main chemical component of cannabis, cannabidiol (CBD), has been shown to have antitumor properties. The present study examined the in vitro effects of CBD on human gastric cancer SGC-7901 cells. We found that CBD significantly inhibited the proliferation and colony formation of SGC-7901 cells. Further investigation showed that CBD significantly upregulated ataxia telangiectasia-mutated gene (ATM) and p53 protein expression and downregulated p21 protein expression in SGC-7901 cells, which subsequently inhibited the levels of CDK2 and cyclin E, thereby resulting in cell cycle arrest at the G0–G1 phase. In addition, CBD significantly increased Bax expression levels, decreased Bcl-2 expression levels and mitochondrial membrane potential, and then upregulated the levels of cleaved caspase-3 and cleaved caspase-9, thereby inducing apoptosis in SGC-7901 cells. Finally, we found that intracellular reactive oxygen species (ROS) increased after CBD treatment. These results indicated that CBD could induce G0–G1 phase cell cycle arrest and apoptosis by increasing ROS production, leading to the inhibition of SGC-7901 cell proliferation, thereby suggesting that CBD may have therapeutic effects on gastric cancer.

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S-Phase Cell Cycle Arrest, Apoptosis, and Molecular Mechanisms of Aplasia Ras homolog Member I–Induced Human Ovarian Cancer SKOV3 Cell Lines

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000105 ◽

2014 ◽

Vol 24 (4) ◽

pp. 629-634 ◽

Cited By ~ 10

Author(s):

Qiaoying Zhu ◽

Jianming Hu ◽

Huijuan Meng ◽

Yufei Shen ◽

Jinhua Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Molecular Mechanisms ◽

Significant Inhibition ◽

S Phase ◽

Phase Cell ◽

Cell Cycle Distribution ◽

Human Ovarian Cancer ◽

Skov3 Cell ◽

Skov3 Cells

ObjectiveAplasia Ras homolog member I (ARHI) is associated with human ovarian cancer (HOC) growth and proliferation; however, the mechanisms are unclear. The purpose of this study was to investigateARHIeffects in HOC SKOV3 cells.MethodsWe transfected SKOV3 cells with PIRES2-EGFP-ARHI and measured growth inhibition rates, cell cycle distribution, apoptosis rates, and expression of P-STAT3 (phosphorylated signal transduction and activators of transcription 3) and P-ERK (phosphorylated extracellular signal regulated protein kinase).ResultsOur data showed significant inhibition of growth, significantly increased S-phase arrest and apoptosis rates, and reduction of P-STAT3 and P-ERK1/2 expression levels.ConclusionsWe propose the mechanism may involveARHI-induced phosphorylation of ERK1/2 and STAT3 protein kinases, thereby blocking proliferation signaling pathways, to induce HOC SKOV3 apoptosis.

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