scholarly journals Identification of cell cycle dependent methotrexate resistance in placenta site trophoblastic tumors

2020 ◽  
Author(s):  
Jing Xu ◽  
Ling Zhang ◽  
Qiyu Liu ◽  
Luyao Ren ◽  
Ke Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Fold Increase ◽  
Cycle Arrest ◽  
Pdx Model ◽  
Ic50 Value ◽  
Cycle Dependent

Abstract Background The purpose is to study the mechanism of chemotherapy resistance in Placental site trophoblastic tumor(PSTT).Methods We established PSTT cell lines by primary culture of a surgically resected PSTT tissues and identified the expression of immune-phenotype markers(HLA-G, β-catenin, CD146, Muc4, hPL, hCG) by immunofluorescence. We measured the IC50 value of methotrexate(MTX), etoposide(VP-16), actinomycin-D(Act-D), cisplatin(DDP), fluorouracil(5-FU) and paclitaxel(TAX) in PSTTs and used a special Mini patient-derived xenograft (Mini PDX) model to evaluate effectiveness of these drugs in vivo. Given that MTX is a cell cycle-dependent chemotherapeutic, we analyzed cell cycle characteristics of PSTT and choriocarcinoma cell lines by flow cytometry and then analyzed RNA profiles and WGS data of the PSTT cell lines to identify the potential mechanism.Results We identified the expression of HLA-G, β-catenin, CD146, hPL and hCG in PSTT cell lines. The IC50 value of MTX was 4.922 mg/ml in PSTT-1, 4.525 mg/ml in PSTT-2, 5.117 mg/ml in PSTT-3, 0.0166 µg/ml in JEG-3 cells (p༜0.001), and 0.01 µg/ml in JAR cells (p༜0.001), with nearly 50,000-fold increase in PSTTs than in choriocarcinoma, indicating that PSTTs are resistant to MTX in vitro. The Mini PDX model revealed that PSTTs are also resistant to MTX in vivo. Cell cycle analysis showed dysregulation of G1/S transition and cell cycle arrest in PSTT cell lines. RNA sequencing profile also identified cell cycle-associated genes which were differentially expressed in PSTT cells than in choriocarcinoma cell.Conclusions We found PSTTs are resistant to MTX in vitro and in vivo compared to choriocarcinoma. Mechanisms could be focused on dysregulation of the G1/S transition and cell cycle arrest.

scholarly journals Menadione reduces CDC25B expression and promotes tumor shrinkage in gastric cancer

2020 ◽  
Vol 13 ◽  
pp. 175628481989543
Author(s):  
Amanda Braga Bona ◽  
Danielle Queiroz Calcagno ◽  
Helem Ferreira Ribeiro ◽  
José Augusto Pereira Carneiro Muniz ◽  
Giovanny Rebouças Pinto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Gastric Carcinogenesis ◽  
In Vivo Experiments ◽  
Cycle Arrest

Background: Gastric cancer is one of the most incident types of cancer worldwide and presents high mortality rates and poor prognosis. MYC oncogene overexpression is a key event in gastric carcinogenesis and it is known that its protein positively regulates CDC25B expression which, in turn, plays an essential role in the cell division cycle progression. Menadione is a synthetic form of vitamin K that acts as a specific inhibitor of the CDC25 family of phosphatases. Methods: To better understand the menadione mechanism of action in gastric cancer, we evaluated its molecular and cellular effects in cell lines and in Sapajus apella, nonhuman primates from the new world which had gastric carcinogenesis induced by N-Methyl-N-nitrosourea. We tested CDC25B expression by western blot and RT-qPCR. In-vitro assays include proliferation, migration, invasion and flow cytometry to analyze cell cycle arrest. In in-vivo experiments, in addition to the expression analyses, we followed the preneoplastic lesions and the tumor progression by ultrasonography, endoscopy, biopsies, histopathology and immunohistochemistry. Results: Our tests demonstrated menadione reducing CDC25B expression in vivo and in vitro. It was able to reduce migration, invasion and proliferation rates, and induce cell cycle arrest in gastric cancer cell lines. Moreover, our in-vivo experiments demonstrated menadione inhibiting tumor development and progression. Conclusions: We suggest this compound may be an important ally of chemotherapeutics in the treatment of gastric cancer. In addition, CDC25B has proven to be an effective target for investigation and development of new therapeutic strategies for this malignancy.

scholarly journals Lenvatinib Inhibits Intrahepatic Cholangiocarcinoma Growth via Gadd45a-Mediated Cell Cycle Arrest

2021 ◽  
Author(s):  
Xia Yan ◽  
Dan Wang ◽  
Liping Zhuang ◽  
Peng Wang ◽  
Zhiqiang Meng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Primary Liver Cancer ◽  
Transcriptional Profiling ◽  
Cycle Arrest

Abstract Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, and its 5-year survival rate is less than 10%. Fibroblast growth factor receptor (FGFR) changes have been observed in 6%-50% of ICC patients, and patients with FGFR mutations have been shown to have more inert tumour biological activity than patients with wild-type FGFRs. Thus, as a pan-FGFR inhibitor, lenvatinib is supposed to play an anti-tumour role in ICC. However, no relevant experiments have been reported.Methods: Patients derived xenograft (PDX) model and cell line derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyse the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism.Reaults: In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G0/G1 phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC.Conclusion: Our work firstly found that lenvatinib exerted excellent antitumor effect on ICC, mainly via inducing Gadd45a mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC.

scholarly journals Apoptosis Induction, Cell Cycle Arrest and in Vitro Anticancer Activity of Gonothalamin in a Cancer Cell Lines

2012 ◽  
Vol 13 (10) ◽  
pp. 5131-5136 ◽  
Author(s):  
Aied M. Alabsi ◽  
Rola Ali ◽  
Abdul Manaf Ali ◽  
Sami Abdo Radman Al-Dubai ◽  
Hazlan Harun ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Anticancer Activity ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Apoptosis Induction ◽  
Cycle Arrest

Oleiferasaponin C6 from the seeds of Camellia oleifera Abel.: a novel compound inhibits proliferation through inducing cell-cycle arrest and apoptosis on human cancer cell lines in vitro

RSC Advances ◽  
2016 ◽  
Vol 6 (94) ◽  
pp. 91386-91393 ◽  
Author(s):  
Jianfa Zong ◽  
Dongxu Wang ◽  
Weiting Jiao ◽  
Liang Zhang ◽  
Guanhu Bao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Camellia Oleifera ◽  
Human Cancer Cell Lines ◽  
Cycle Arrest

Oleiferasaponin C6 was isolated from Camellia oleifera Abel. and inhibits proliferation through inducing cell-cycle arrest and apoptosis on cancer cell lines in vitro.

Bound polyphenol extracted from jujube pulp triggers mitochondria-mediated apoptosis and cell cycle arrest of HepG2 cell in vitro and in vivo

2019 ◽  
Vol 53 ◽  
pp. 187-196 ◽  
Author(s):  
Shuhua Shan ◽  
Yue Xie ◽  
Huiling Zhao ◽  
Jinping Niu ◽  
Sheng Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Hepg2 Cell ◽  
Cycle Arrest

scholarly journals Cyperus articulatus L. (Cyperaceae) Rhizome Essential Oil Causes Cell Cycle Arrest in the G2/M Phase and Cell Death in HepG2 Cells and Inhibits the Development of Tumors in a Xenograft Model

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2687
Author(s):  
Mateus L. Nogueira ◽  
Emilly J. S. P. de Lima ◽  
Asenate A. X. Adrião ◽  
Sheila S. Fontes ◽  
Valdenizia R. Silva ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gas Chromatography ◽  
Cell Death ◽  
Liver Cancer ◽  
Essential Oil ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Hepg2 Cells ◽  
Cycle Arrest

Cyperus articulatus L. (Cyperaceae), popularly known in Brazil as “priprioca” or “piriprioca”, is a tropical and subtropical plant used in popular medical practices to treat many diseases, including cancer. In this study, C. articulatus rhizome essential oil (EO), collected from the Brazilian Amazon rainforest, was addressed in relation to its chemical composition, induction of cell death in vitro and inhibition of tumor development in vivo, using human hepatocellular carcinoma HepG2 cells as a cell model. EO was obtained by hydrodistillation using a Clevenger-type apparatus and characterized qualitatively and quantitatively by gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography with flame ionization detection (GC-FID), respectively. The cytotoxic activity of EO was examined against five cancer cell lines (HepG2, HCT116, MCF-7, HL-60 and B16-F10) and one non-cancerous one (MRC-5) using the Alamar blue assay. Cell cycle distribution and cell death were investigated using flow cytometry in HepG2 cells treated with EO after 24, 48 and 72 h of incubation. The cells were also stained with May–Grunwald–Giemsa to analyze the morphological changes. The anti-liver-cancer activity of EO in vivo was evaluated in C.B-17 severe combined immunodeficient (SCID) mice with HepG2 cell xenografts. The main representative substances of this EO sample were muskatone (11.6%), cyclocolorenone (10.3%), α-pinene (8.26%), pogostol (6.36%), α-copaene (4.83%) and caryophyllene oxide (4.82%). EO showed IC50 values for cancer cell lines ranging from 28.5 µg/mL for HepG2 to >50 µg/mL for HCT116, and an IC50 value for non-cancerous of 46.0 µg/mL (MRC-5), showing selectivity indices below 2-fold for all cancer cells tested. HepG2 cells treated with EO showed cell cycle arrest at G2/M along with internucleosomal DNA fragmentation. The morphological alterations included cell shrinkage and chromatin condensation. Treatment with EO also increased the percentage of apoptotic-like cells. The in vivo tumor mass inhibition rates of EO were 46.5–50.0%. The results obtained indicate the anti-liver-cancer potential of C. articulatus rhizome EO.

scholarly journals Growth Suppression by Acute PromyelocyticLeukemia-Associated Protein PLZF Is Mediated by Repression ofc-mycExpression

2003 ◽  
Vol 23 (24) ◽  
pp. 9375-9388 ◽  
Author(s):  
Melanie J. McConnell ◽  
Nathalie Chevallier ◽  
Windy Berkofsky-Fessler ◽  
Jena M. Giltnane ◽  
Rupal B. Malani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Target Genes ◽  
Ectopic Expression ◽  
Growth Suppression ◽  
Quiescent State ◽  
Cycle Arrest

ABSTRACT The transcriptional repressor PLZF was identified by its translocation with retinoic acid receptor alpha in t(11;17) acute promyelocytic leukemia (APL). Ectopic expression of PLZF leads to cell cycle arrest and growth suppression, while disruption of normal PLZF function is implicated in the development of APL. To clarify the function of PLZF in cell growth and survival, we used an inducible PLZF cell line in a microarray analysis to identify the target genes repressed by PLZF. One prominent gene identified was c-myc. The array analysis demonstrated that repression of c-myc by PLZF led to a reduction in c-myc-activated transcripts and an increase in c-myc-repressed transcripts. Regulation of c-myc by PLZF was shown to be both direct and reversible. An interaction between PLZF and the c-myc promoter could be detected both in vitro and in vivo. PLZF repressed the wild-type c-myc promoter in a reporter assay, dependent on the integrity of the binding site identified in vitro. PLZF binding in vivo was coincident with a decrease in RNA polymerase occupation of the c-myc promoter, indicating that repression occurred via a reduction in the initiation of transcription. Finally, expression of c-myc reversed the cell cycle arrest induced by PLZF. These data suggest that PLZF expression maintains a cell in a quiescent state by repressing c-myc expression and preventing cell cycle progression. Loss of this repression through the translocation that occurs in t(11;17) would have serious consequences for cell growth control.

Lobetyol activate MAPK pathways associated with G 1 /S cell cycle arrest and apoptosis in MKN45 cells in vitro and in vivo

2016 ◽  
Vol 81 ◽  
pp. 120-127 ◽  
Author(s):  
Jie Shen ◽  
XinGang Lu ◽  
WangChun Du ◽  
Jun Zhou ◽  
HongFu Qiu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Mapk Pathways ◽  
Cycle Arrest
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