scholarly journals Janerin Induces Cell Cycle Arrest at the G2/M Phase and Promotes Apoptosis Involving the MAPK Pathway in THP-1, Leukemic Cell Line

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7555
Author(s):  
Mohammad Z. Ahmed ◽  
Fahd A. Nasr ◽  
Wajhul Qamar ◽  
Omar M. Noman ◽  
Javed Masood Khan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Mapk Pathway ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
M Phase ◽  
Human Leukemic Cells ◽  
Dose Dependent

Janerin is a cytotoxic sesquiterpene lactone that has been isolated and characterized from different species of the Centaurea genus. In this study, janerin was isolated form Centaurothamnus maximus, and its cytotoxic molecular mechanism was studied in THP-1 human leukemic cells. Janerin inhibited the proliferation of THP-1 cells in a dose-dependent manner. Janerin caused the cell cycle arrest at the G2/M phase by decreasing the CDK1/Cyclin-B complex. Subsequently, we found that janerin promoted THP-1 cell death through apoptosis as indicated by flow cytometry. Moreover, apoptosis induction was confirmed by the upregulation of Bax, cleaved PARP-1, and cleaved caspase 3 and the downregulation of an anti-apoptotic Bcl-2 biomarker. In addition, immunoblotting indicated a dose dependent upregulation of P38-MAPK and ERK1/2 phosphorylation during janerin treatment. In conclusion, we have demonstrated for the first time that janerin may be capable of inducing cell cycle arrest and apoptosis through the MAPK pathway, which would be one of the mechanisms underlying its anticancer activity. As a result, janerin has the potential to be used as a therapeutic agent for leukemia.

SMBA1, a Bax Activator, Induces Cell Cycle Arrest and Apoptosis in Malignant Glioma Cells

Pharmacology ◽  
2019 ◽  
Vol 105 (3-4) ◽  
pp. 164-172
Author(s):  
Shuangbo Fan ◽  
Qian Xu ◽  
Liang Wang ◽  
Yulin Wan ◽  
Sheng Qiu
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Biological Effects ◽  
Cyclin B1 ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
Cycle Arrest ◽  
Intrinsic Apoptosis Pathway ◽  
Induced Apoptosis ◽  
Dose Dependent

SMBA1 (small-molecule Bax agonists 1), a small molecular activator of Bax, is a potential anti-tumour agent. In the present study, we investigated the biological effects of SMBA1 on glioblastoma (GBM) cells. SMBA1 reduced the viabilities of U87MG, U251 and T98G cells in a time- and dose-dependent manner. Moreover, treatment with SMBA1 induced cell cycle arrest at the G2/M phase transition, accompanied by the downregulation of Cdc25c and cyclin B1 and the upregulation of p21. SMBA1 also induced apoptosis of GBM cells in a dose-dependent manner. Mechanistically, SMBA1 induced apoptosis via the intrinsic pathway. Silencing of Bax or ectopic expression of Bcl-2 significantly inhibited SMBA1-induced apoptosis. Moreover, SMBA1 inhibited the growth of U87MG xenograft tumours in vivo. Overall, SMBA1 shows anti-proliferative effects against GBM cells through activation of the intrinsic apoptosis pathway.

scholarly journals Synthesis, cytotoxicity, apoptosis and cell cycle arrest of a ruthenium multi-substituted Keggin-type polyoxotungstate

2021 ◽  
Author(s):  
Shifang Jia ◽  
Yanzhen Wen ◽  
Xiuli Hao ◽  
Yan Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Lung Fibroblasts ◽  
Dependent Manner ◽  
Cytotoxic Potential ◽  
Cycle Arrest ◽  
Elemental Analyses ◽  
Keggin Anions ◽  
Dose Dependent

Abstract The ruthenium multi-substituted polyoxotungstate with chemical formulae of K7[SiW9O37Ru4(H2O)3Cl3]·15H2O (S1) was synthesized by a conventional aqueous solution containing the trilacunary Keggin-anions β-Na9HSiW9O34·12H2O(S2) and RuCl3·nH2O(S3). Compound S1 was characterized by elemental analyses, EDS, TG analyses, IR, UV/Vis and XPS. The cytotoxic potential of compound S1 was tested on C33A, DLD-1, HepG-2 cancer cells and human normal embryonic lung fibroblasts cell MRC-5. The viability of the treated cells was evaluated by MTT assay. The mode of cell death was assessed by morphological study of DNA damage and apoptosis assays. Compound S1 induced cell death in a dose-dependent manner, and the mode of cell death was essentially apoptosis though necrosis was also noticed. Cell cycle analysis by flow cytometry indicated that compound S1 caused cell cycle arrest and accumulated cells in S phase.

Honokiol, a chemopreventive agent against skin cancer, induces cell cycle arrest and apoptosis in human epidermoid A431 cells

2011 ◽  
Vol 236 (11) ◽  
pp. 1351-1359 ◽  
Author(s):  
Chandeshwari Chilampalli ◽  
Ruth Guillermo ◽  
Radhey S Kaushik ◽  
Alan Young ◽  
Gudiseva Chandrasekher ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Skin Cancer ◽  
Cell Cycle Arrest ◽  
Squamous Carcinoma ◽  
Ultraviolet B ◽  
Dependent Manner ◽  
A431 Cells ◽  
Squamous Carcinoma Cells ◽  
Cycle Arrest ◽  
M Phase

Honokiol is a plant lignan isolated from bark and seed cones of Magnolia officinalis. Recent studies from our laboratory indicated that honokiol pretreatment decreased ultraviolet B-induced skin cancer development in SKH-1 mice. The aim of the present investigation was to study the effects of honokiol on human epidermoid squamous carcinoma A431 cells and to elucidate possible mechanisms involved in preventing skin cancer. A431 cells were pretreated with different concentrations of honokiol for a specific time period and investigated for effects on apoptosis and cell cycle analysis. Treatment with honokiol significantly decreased cell viability and cell proliferation in a concentration- and time-dependent manner. Honokiol pretreatment at 50 μmol/L concentration induced G0/G1 cell cycle arrest significantly ( P < 0.05) and decreased the percentage of cells in the S and G2/M phase. Honokiol down-regulated the expression of cyclin D1, cyclin D2, Cdk2, Cdk4 and Cdk6 proteins and up-regulated the expression of Cdk's inhibitor proteins p21 and p27. Pretreatment of A431 cells with honokiol leads to induction of apoptosis and DNA fragmentation. These findings indicate that honokiol provides its effects in squamous carcinoma cells by inducing cell cycle arrest at G0/G1 phase and apoptosis.

scholarly journals Sulforaphane Causes Cell Cycle Arrest and Apoptosis in Human Glioblastoma U87MG and U373MG Cell Lines under Hypoxic Conditions

2021 ◽  
Vol 22 (20) ◽  
pp. 11201
Author(s):  
Giulia Sita ◽  
Agnese Graziosi ◽  
Patrizia Hrelia ◽  
Fabiana Morroni
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Hypoxic Condition ◽  
Primary Brain Tumor ◽  
Dependent Manner ◽  
Hypoxic Conditions ◽  
Cycle Arrest ◽  
Extracellular Signal ◽  
Dose Dependent

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor. The median survival rate from diagnosis ranges from 15 to 17 months because the tumor is resistant to most therapeutic strategies. GBM exhibits microvascular hyperplasia and pronounced necrosis triggered by hypoxia. Sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, has already demonstrated the ability to inhibit cell proliferation, by provoking cell cycle arrest, and leading to apoptosis in many cell lines. In this study, we investigated the antineoplastic effects of SFN [20–80 μM for 48 h] in GBM cells under normoxic and hypoxic conditions. Cell viability assays, flow cytometry, and Western blot results revealed that SFN could induce apoptosis of GBM cells in a dose-dependent manner, under both conditions. In particular, SFN significantly induced caspase 3/7 activation and DNA fragmentation. Moreover, our results demonstrated that SFN suppressed GBM cells proliferation by arresting the cell cycle at the S-phase, also under hypoxic condition, and that these effects may be due in part to its ability to induce oxidative stress by reducing glutathione levels and to increase the phosphorylation of extracellular signal-regulated kinases (ERKs). Overall, we hypothesized that SFN treatment might serve as a potential therapeutic strategy, alone or in combination, against GBM.

WP-1066, a Next-Generation Member of JAK-Stat Inhibitors, Induces Cell Cycle Arrest, Abrogates Proliferation, and Induces Apoptosis of Acute Myeloid Leukemia (AML) Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1169-1169
Author(s):  
Alessandra Ferrajoli ◽  
Stefan Faderl ◽  
Quin Van ◽  
David M. Harris ◽  
Waldemar Priebe ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
K562 Cells ◽  
Leukemia Cells ◽  
Parp Cleavage ◽  
Dependent Manner ◽  
Stat Proteins ◽  
Cycle Arrest ◽  
Dose Dependent ◽  
Stat Pathway

Abstract Janus kinases (JAK) are tyrosine kinases associated with both cytokine receptors and downstream signal transducer and activator of transcription (Stat) proteins. Upon activation of JAK by a variety of cytokines and growth factors, Stats translocate to the nucleus and promote transcription of target genes. Constitutive activation of Stat proteins in AML has been associated with poor prognosis and AG490, an inhibitor of this pathway, was shown to suppress AML cell proliferation in vitro. WP-1066 represents a further development of AG490 with biological activity at significantly lower concentrations. Therefore, we studied the effects of WP-1066 on the AML cell lines OCIM2 and K562 and on fresh bone marrow aspirates obtained from five newly diagnosed AML patients. We found that WP-1066 inhibited the proliferation of OCIM2 and K562 cells and of fresh marrow AML blast colony-forming cells in a dose-dependent fashion at concentrations ranging from 0.5 to 3 μM. WP-1066 completely abrogated the growth of leukemia cells at a concentration of 3 μM. Furthermore, WP-1066 induced a cell cycle arrest of OCIM2 and K562 cells. Incubation of AML cells with 2 μM of WP-1066 resulted in a time-dependent accumulation of OCIM2 and K562 cells in the sub-G0 phase of the cell cycle. Those leukemia cells underwent apoptotic cell death as assessed by annexin V-FITC. Incubation of OCIM2 cells with 0.5 to 3 μM WP-1066 for 2 hours induced a dose-dependent apoptosis in 52% of the cells. A 4 hour exposure of either OCIM2 or K562 cells to 2 μM of WP-1066 induced caspase 3 activation and PARP cleavage. As expected, WP-1066 inhibited Stat3 and Stat5 phosphorylation in K562 and OCIM2 cells both in a time- and dose-dependent manner, confirming that inhibition of the JAK-Stat pathway is its mechanism of action. Overall, our data showing that WP-1066 inhibits the JAK-Stat pathway, suppresses proliferation, induces cell cycle arrest and apoptosis of AML cells, suggest that the activity of this compound warrants further exploitation aimed at developing WP-1066 for future therapy of AML.

scholarly journals Endophytic Streptomyces sp. LRE541 isolated from Lilium davidii var. Unicolor Cotton as a Cell Factory for Antimicrobials and Anticarcinogens with Inducing Apoptosis and Cell Cycle Arrest Properties

2020 ◽  
Author(s):  
Aiai Ma ◽  
Xinge Qi ◽  
Kan Jiang ◽  
Bin Chen ◽  
Junlin Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Bioactive Metabolites ◽  
Cell Factory ◽  
Dependent Manner ◽  
Etoac Extract ◽  
Cycle Arrest ◽  
Dose Dependent ◽  
Lilium Davidii

Abstract Background: Endophytic actinomycetes, as emerging sources of bioactive metabolites, play a vital role in pharmaceutical development. Recent reports demonstrated that endophytic Streptomyces isolates could yield compounds with potent anticancer and antimicrobial properties that may be developed into chemotherapeutic drugs. Our study displayed that Streptomyces sp. LRE541 obtained from the root tissues of Lilium davidii var. unicolor Cotton, could be a potential source of anticarcinogens and antimicrobials.Results: Isolate LRE541 was characterized and identified as belonging to the genus Streptomyces based on the 16S rDNA sequence analysis, with highest sequence similarity to Streptomyces tauricus JCM4837T (98.81%). It produced extensively branched red substrate and vivid pink aerial hyphae that changed into amaranth, with elliptic spores sessile to the aerial mycelia. The secondary metabolites (EtOAc extract) produced by isolate LRE541 exhibited significant anticancer activities with IC50 values of 0.021, 0.2904, 1.484, 4.861, 6.986, 8.106, 10.87, 12.98, and 16.94 μg/mL against cancer cells RKO, 7901, HepG2, CAL-27, MCF-7, K562, Hela, SW1190 and A549, respectively, evaluated by the MTT assay. In contrast, the EtOAc extract showed less cytotoxicity activity against the normal human pulmonary artery endothelial cell (HPAEC) with an IC50 value of > 20 μg/mL than that of the cancer cells. To further explore the mechanism underlying the decrease in viability of cancer cells following the EtOAc extract treatment, cell apoptosis and cell cycle arrest assays were performed using two cancer cell lines, RKO and 7901. The result demonstrated that the EtOAc extract inhibited cell proliferation of RKO and 7901 cells by causing cell cycle arrest both at the S phase and inducing apoptosis in a dose‑dependent manner. Moreover, the EtOAc extract of isolate LRE541 with the concentrations within 100 μg/mL also possessed the antagonistic activities against E. coli ATCC 25922, MRSA ATCC 25923, P. aeruginosa and C. albicans ATCC 66415, and the antagonistic potent against the tested pathogens all displayed a dose-dependent manner. The UHPLC-MS/MS analysis of the EtOAc extract revealed that the presence of antitumor, potential antitumor and antimicrobial compounds could account for the potent antineoplasmic and antagonistic properties of the extract. Conclusion: This study provides the potential therapeutic applications of the bioactive metabolites from Streptomyces sp. LRE541 as novel antimicrobial and anticancer agents.

The PAF Complex Regulation of Prmt5 Facilitates Leukemic Progression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3914-3914
Author(s):  
Justin Serio ◽  
Wei Chen ◽  
Maria Mysliwski ◽  
Lili Chen ◽  
James Ropa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Conflicts Of Interest ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Cytokine Signaling ◽  
Cycle Arrest ◽  
Acute Myeloid

Abstract Acute myeloid leukemias have been linked with dysregulated epigenetic landscapes sometimes attributed to altered functions of epigenetic regulators. The Polymerase-Associated Factor complex (PAFc) is an epigenetic regulator involved in transcriptional initiation, elongation and termination and directly interacts with the CTD of RNA Pol II. The complex is comprised of 6 subunits in human cells, Paf1, Cdc73, Ctr9, Leo1, Rtf1 and Ski8. Many of these subunits have key roles in a variety of cancers including acute myeloid leukemia (AML). We have previously shown the relevance of the PAFc in MLL-rearranged leukemias where its interaction with MLL fusion-proteins is required for leukemic progression in vitro and in vivo (Muntean et al. 2013 Blood, Muntean et al. 2010 Cancer Cell). However, little is known about the gene programs controlled by the PAFc and how these contribute to leukemogenesis. Here we identify Prmt5, an arginine methyltransferase, as a direct downstream target gene of the PAFc. Prmt5 is upregulated in variety of cancers and has been linked to cell cycle progression and activation of known oncoproteins. In addition, Prmt5 has been implicated in AML and is essential for normal hematopoiesis where loss of Prmt5 induces bone marrow aplasia due to impaired cytokine signaling (Tarighat et al. 2015 Leukemia, Liu et al. 2015 J Clin Invest). Our work establishes a major role for the PAFc in regulating Prmt5 expression in AML. We observe that excision of the Cdc73 subunit of the PAFc results in reduced proliferation, the induction of differentiation, cell cycle arrest, and a mild increase in apoptosis. Several key epigenetic marks are reduced globally upon loss of Cdc73 including H4R3me2s, a modification catalyzed by Prmt5. RNA sequencing and bioinformatics analysis using GSEA, revealed that loss of Cdc73 led to increased expression of a gene program associated with hematopoietic differentiation, in agreement with our cellular characterization. In addition, the downregulation of a methyltransferase gene program was detected upon Cdc73 excision. Included in this signature were several members of the Prmt family. Analysis of changes in expression following loss of Cdc73 and functional relevance in MLL-AF9 leukemic cells led us to Prmt5 as a gene critically important in AML cells and modulated by the PAFc. To interrogate the function of Prmt5 in AML cells, we performed shRNA knockdown experiments which resulted in reduced proliferation, reduced cell fitness, G1 cell cycle arrest and global reduction H4R3me2s. ChIP experiments revealed that the PAFc localizes to the Prmt5 locus in mouse and human derived leukemic cells. Further, preliminary data suggests the MLL-AF9 fusion protein also localizes to the Prmt5 locus and may enhance its transcriptional output. The enzymatic activity of Prmt5 is necessary for AML cell growth as wild type PRMT5 can rescue proliferation of Prmt5 knock-down cells while a catalytic dead mutant cannot. Furthermore, we have observed that knockdown of Prmt5 increases the disease latency of Hoxa9/Meis1 induced leukemia in vivo. Utilizing a commercially available inhibitor for Prmt5, EPZ015666 (Chan-Pembre et al. 2015 Nat Chem Bio), we show pharmacologic inhibition of PRMT5 reduces the growth of a spectrum of human leukemic cell lines, suggesting PRMT5 is important for multiple subtypes of AML. Overall, our findings elucidate the PAFc as a regulator of Prmt5 expression that is necessary for the maintenance of AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Corosolic acid induces potent anti-cancer effects in CaSki cervical cancer cells through the induction of apoptosis, cell cycle arrest and PI3K/Akt signalling pathway

2016 ◽  
Vol 11 (2) ◽  
pp. 453 ◽  
Author(s):  
Yong Qian Xu ◽  
Jian Hai Zhang ◽  
Xing Sheng Yang
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Video Clip ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
Corosolic Acid ◽  
Cervical Cancer Cells ◽  
Dose Dependent

<p class="Abstract">The main objective of the present study was to investigate the anti-tumor activity of corosolic acid in CaSki human cervical cancer cells. Fluorescence and phase contrast microscopic techniques were used to study the effect of the compound on cellular morphology and apoptosis. Results revealed that corosolic acid exerted potent, dose- and time-dependent growth inhibitory effects in CaSki cell proliferation. Cells got detached from one another making clusters of small number of cells floating in the medium. After the cells were treated with 10, 50 and 100 µM concentrations of corosolic acid, cells began to emit orange red fluorescence more heavily at the centre of cells indicating apoptosis. Corosolic acid also induced G2/M cell cycle arrest in a dose-dependent manner. Increasing doses of corosolic acid treatment to these cells resulted in significant and dose-dependent down-regulation of PI3K and Akt protein expressions.</p><p><strong>Video Clip</strong></p><p><a href="https://youtube.com/v/N4EivZECRZE">Western blot assay</a>: 2 min 1 sec  </p>

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