scholarly journals A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy

2021 ◽  
Author(s):  
Nicolas Fischer ◽  
Ean-Jeong Seo ◽  
Sara Abdelfatah ◽  
Edmond Fleischer ◽  
Anette Klinger ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Virtual Screening ◽  
Small Molecules ◽  
Large Scale ◽  
Differentiation Therapy ◽  
P53 Expression ◽  
Microscale Thermophoresis ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Mcf 7

SummaryIntroduction Differentiation therapy is a promising strategy for cancer treatment. The translationally controlled tumor protein (TCTP) is an encouraging target in this context. By now, this field of research is still at its infancy, which motivated us to perform a large-scale screening for the identification of novel ligands of TCTP. We studied the binding mode and the effect of TCTP blockade on the cell cycle in different cancer cell lines. Methods Based on the ZINC-database, we performed virtual screening of 2,556,750 compounds to analyze the binding of small molecules to TCTP. The in silico results were confirmed by microscale thermophoresis. The effect of the new ligand molecules was investigated on cancer cell survival, flow cytometric cell cycle analysis and protein expression by Western blotting and co-immunoprecipitation in MOLT-4, MDA-MB-231, SK-OV-3 and MCF-7 cells. Results Large-scale virtual screening by PyRx combined with molecular docking by AutoDock4 revealed five candidate compounds. By microscale thermophoresis, ZINC10157406 (6-(4-fluorophenyl)-2-[(8-methoxy-4-methyl-2-quinazolinyl)amino]-4(3H)-pyrimidinone) was identified as TCTP ligand with a KD of 0.87 ± 0.38. ZINC10157406 revealed growth inhibitory effects and caused G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. ZINC10157406 (2 × IC50) downregulated TCTP expression by 86.70 ± 0.44% and upregulated p53 expression by 177.60 ± 12.46%. We validated ZINC10157406 binding to the p53 interaction site of TCTP and replacing p53 by co-immunoprecipitation. Discussion ZINC10157406 was identified as potent ligand of TCTP by in silico and in vitro methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differentiation therapy in oncology.

Ganoderma lucidum Extract Induces G1 Cell Cycle Arrest, and Apoptosis in Human Breast Cancer Cells

2012 ◽  
Vol 40 (03) ◽  
pp. 631-642 ◽  
Author(s):  
Guosheng Wu ◽  
Zhengming Qian ◽  
Jiajie Guo ◽  
Dejun Hu ◽  
Jiaolin Bao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Mcf 7

Ganoderma lucidum (Fr.) Karst is a traditional Chinese herb that has been widely used for centuries to treat various diseases including cancer. Herein, an ethanol-soluble and acidic component (ESAC), which mainly contains triterpenes, was prepared from G. lucidum and its anti-tumor effects in vitro were tested on human breast cancer cells. Our results showed that ESAC reduced the cell viability of MCF-7 and MDA-MB-231 cells in a concentration-dependent manner with IC50 of about 100 μg/mL and 60 μg/mL, respectively. DNA damage was detected by Comet assay and the increased expression of γ-H2AX after ESAC treatment was determined in MCF-7 cells. Moreover, ESAC effectively mediated G1 cell cycle arrest in both concentration- and time-dependent manners and induced apoptosis as determined by Hoechst staining, DNA fragment assay and Western blot analysis in MCF-7 cells. In conclusion, ESAC exerts anti-proliferation effects by inducing DNA damage, G1 cell cycle arrest and apoptosis in human breast cancer cells.

(E)-1-(3,4-dihydroxyphenethyl)-3-styrylurea inhibits proliferation of MCF-7 cells through G1 cell cycle arrest and mitochondria-mediated apoptosis

2010 ◽  
Vol 30 (4) ◽  
pp. 303-310 ◽  
Author(s):  
Ji-Yeon Yu ◽  
Ji-Hae Kim ◽  
Tae-Geum Kim ◽  
Beom-Tae Kim ◽  
Yong-Suk Jang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Mcf 7

scholarly journals Dentatin isolated from Clausena excavata induces apoptosis in MCF-7 cells through the intrinsic pathway with involvement of NF-κB signalling and G0/G1 cell cycle arrest: A bioassay-guided approach

2013 ◽  
Vol 145 (1) ◽  
pp. 343-354 ◽  
Author(s):  
Ismail Adam Arbab ◽  
Ahmad Bustamam Abdul ◽  
Mohd Aspollah Sukari ◽  
Rasedee Abdullah ◽  
Suvitha Syam ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Intrinsic Pathway ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Mcf 7

Synthesis and Identification of Small Molecules that Potently Induce Apoptosis in Melanoma Cells through G1 Cell Cycle Arrest

2005 ◽  
Vol 127 (24) ◽  
pp. 8686-8696 ◽  
Author(s):  
Robin S. Dothager ◽  
Karson S. Putt ◽  
Brittany J. Allen ◽  
Benjamin J. Leslie ◽  
Vitaliy Nesterenko ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Small Molecules ◽  
Cell Cycle Arrest ◽  
Melanoma Cells ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Rice Hull Extracts Inhibit Proliferation of MCF-7 Cells with G1 Cell Cycle Arrest in Parallel with Their Antioxidant Activity

2015 ◽  
Vol 18 (3) ◽  
pp. 314-323 ◽  
Author(s):  
Nam-Jin Chung ◽  
Ki-Choon Choi ◽  
Seung-Ah Lee ◽  
Jin-A Baek ◽  
Jeong-Chae Lee
Keyword(s):  
Cell Cycle ◽  
Antioxidant Activity ◽  
Cell Cycle Arrest ◽  
Rice Hull ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Mcf 7

scholarly journals Novel Small Molecules Capable of Blocking mtRAS-Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Namkyoung Kim ◽  
Injae Shin ◽  
Younghoon Kim ◽  
Eunhye Jeon ◽  
Jiwon Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Small Molecules ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Proliferative Activity ◽  
Kinase Inhibitor ◽  
Cycle Arrest ◽  
Binding Pockets ◽  
G1 Cell Cycle Arrest ◽  
Ht 29

RAS mutants are involved in approximately 30% of all human cancers and have been regarded as undruggable targets owing to relatively smooth protein surface and obscure binding pockets. In our previous study, we have demonstrated that GNF-7, a multi-targeted kinase inhibitor, possesses potent anti-proliferative activity against Ba/F3 cells transformed with NRAS-G12D. Based on our further analysis using Ba/F3 cells transformed with mtRAS, we discovered a series of pyrimido[4,5-d]pyrimidin-2-one analogues as mtRAS-signaling pathway blockers. In addition, our efforts expanded the assessment to cancer cells with mtRAS, which revealed that these substances are also capable of strongly suppressing the proliferation of various cancer cells harboring KRAS-G12D (AsPC-1), KRAS-G12V (SW480, DU-145), KRAS-G12C (H358), KRAS-G13D (MDA-MB-231), KRAS-Q61L (HT-29), and NRAS-Q61L (OCI-AML3). We herein report novel and potent mtRAS-signaling pathway blockers, SIJ1795 and SIJ1772, possessing 2 to 10-fold increased anti-proliferative activities compared to those of GNF-7 on cancer cells harboring mtRAS as well as on Ba/F3 cells transformed with mtRAS. Both SIJ1795 and SIJ1772 attenuate phosphorylation of RAS downstream molecules (AKT and MEK) and induce apoptosis and G0/G1 cell cycle arrest on cancer cells with mtRAS. Moreover, both substances substantially suppress the migration, invasion, and colony formation of cancer cells harboring mtRAS. Taken together, this study led us to identification of SIJ1795 and SIJ1772 capable of strongly inhibiting mtRAS-signaling pathway on cancer cells harboring mtRAS.

Zn(ii), Cd(ii) and Hg(ii) saccharinate complexes with 2,6-bis(2-benzimidazolyl)pyridine as promising anticancer agents in breast and lung cancer cell lines via ROS-induced apoptosis

2020 ◽  
Vol 49 (23) ◽  
pp. 7842-7851
Author(s):  
Ceyda Icsel ◽  
Veysel T. Yilmaz ◽  
Seyma Aydinlik ◽  
Muhittin Aygun
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Ros Generation ◽  
Lung Cancer Cell ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Induced Apoptosis ◽  
Mcf 7

Highly cytotoxic Zn(ii) and Hg(ii) saccharinate complexes with 2,6-bis(2-benzimidazolyl)pyridine cause G0/G1 cell cycle arrest, excessive ROS generation, and mitochondrial and DNA damage in A549 and MCF-7 cell lines, respectively.

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