scholarly journals The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines

2013 ◽  
Vol 3 (1) ◽  
pp. 36-46 ◽  
Author(s):  
Eva Wessel Stratford ◽  
Jeanette Daffinrud ◽  
Else Munthe ◽  
Russell Castro ◽  
Jo Waaler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Specific Inhibitor ◽  
Osteosarcoma Cell ◽  
Cycle Progression

scholarly journals Delayed Cell Cycle Progression and Apoptosis Induced by Hemicellulase-TreatedAgaricus blazei

2007 ◽  
Vol 4 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Masaki Kawamura ◽  
Hirotake Kasai
Keyword(s):  
Cell Cycle ◽  
P38 Mapk ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Combined Treatment ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Activation Effect ◽  
Cycle Progression ◽  
Fraction H

We examined the effects of hemicellulase-treatedAgaricus blazei(AB fraction H, ABH) on growth of several tumor cell lines. ABH inhibited the proliferation of some cell lines without cytotoxic effects. It markedly prolonged the S phase of the cell cycle. ABH also induced mitochondria-mediated apoptosis in different cell lines. However, it had no impact on the growth of other cell lines. ABH induced strong activation of p38 mitogen-activated protein kinase (MAPK) in the cells in which it evoked apoptosis. On the other hand, ABH showed only a weak p38 activation effect in those cell lines in which it delayed cell cycle progression with little induction of apoptosis. However, p38 MAPK-specific inhibitor inhibited both ABH-induced effects, and ABH also caused apoptosis in the latter cells under conditions of high p38 MAPK activity induced by combined treatment with TNF-α. These results indicate that the responsiveness of p38 MAPK to ABH, which differs between cell lines, determines subsequent cellular responses on cell growth.

Centrosome Aberrations, Disturbed Mitotic Spindle Formation and G1 Arrest in Normal and Leukemic Cells Treated with the SRC/ABL Inhibitor Dasatinib.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2167-2167
Author(s):  
Alice Fabarius ◽  
Michelle Giehl ◽  
Alwin Kraemer ◽  
Oliver Frank ◽  
Martin C. Mueller ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Dermal Fibroblasts ◽  
G1 Arrest ◽  
Osteosarcoma Cell ◽  
Cycle Progression ◽  
Spindle Formation

Abstract Multitargeted ABL inhibitors have been developed to simultaneously inhibit various pathways associated with proliferation in BCR-ABL+ diseases. Dasatinib (Bristol Myers Squibb) is a potent inhibitor targeting ABL, SRC, and other tyrosine kinases. SRC kinases are required for progression through the initial phase of mitosis. Centrosomes play a fundamental role in mitotic spindle organization, chromosome segregation and genetic stability. We sought to evaluate the activity of dasatinib on proliferation, centrosome status, spindle formation, and cell cycle progression in vitro and in vivo. Normal human dermal fibroblasts (NHDF), Chinese hamster embryonal fibroblasts (CHE), and the human osteosarcoma cell line U2OS were treated with serial concentrations (1nM-10μM) of dasatinib for 3 weeks. Effects of dasatinib were compared with data achieved with the ABL inhibitors imatinib (Novartis, 5–20μM) and nilotinib (Novartis, 0.5–20μM), the specific SRC inhibitor PP2 (Calbiochem-Novabiochem, 0.1–2μM), the ABL/LYN inhibitor INNO-406 (Innovive, 0.1–2μM), and solvent control. Bone marrow and peripheral blood samples from 18 patients (pts, 10 m, 8 f; median age 57 yrs, range 26–75) treated with dasatinib (70mg bid) after imatinib failure for a median of 11 mo (range, 3–16) were investigated. 17 pts had chronic myeloid leukemia (CML) in chronic phase. One patient suffered from a gastrointestinal stromal tumor. For comparison, 3 untreated CML pts and 3 healthy individuals were evaluated. Cell proliferation was determined in liquid culture incubated with serial dilutions of the inhibitor. Centrosome morphology and spindle formation were evaluated after pericentrin and α-tubulin staining, respectively. Cell cycle progression was analyzed by FACS and expression of EG5 by immunofluorescence microscopy. Dasatinib induced a G1 cell cycle arrest in all cell lines tested and in pts associated with a shift to 1n DNA ploidy and absence of EG5 as a marker for G2 phase/mitosis. In vitro, centrosomal aberrations and delay of spindle formation were observed in a dose dependent fashion. In pts, centrosome alterations were found in a median of 17% (range, 10–15) of cells. Disturbed spindle formation was observed in 9/18 pts. In comparison, incubation with imatinib and nilotinib was associated with centrosome aberrations but not with defects of spindle formation and G1 arrest. PP2 induced S-phase arrest; centrosome aberrations were observed at higher dosages (1–2 μM) only, spindle formation was not affected. INNO-406 was associated with both centrosome aberrations and disturbed spindle formation. In pharmacological doses, proliferation of BCR-ABL neg. cell lines was inhibited after dasatinib treatment, but not after incubation with imatinib, nilotinib, PP2, or INNO-406. In conclusion, dasatinib blocks the G1/S transition and thereby inhibits cell growth in normal and neoplastic cells. In addition, it induces both centrosomal and spindle aberrations. Effects of dasatinib are not based on SRC inhibition alone but may be associated with the combination of SRC and ABL inhibition or with non-specific effects on multiple kinases. Therefore, dasatinib should be defined as a cytostatic drug with a strong targeted component resulting in a preferential inhibition of cells harboring a specific target, like BCR-ABL.

Polyamine depletion arrests growth of IEC-6 and Caco-2 cells by different mechanisms

2001 ◽  
Vol 281 (1) ◽  
pp. G37-G43 ◽  
Author(s):  
Ramesh M. Ray ◽  
Shirley A. McCormack ◽  
Leonard R. Johnson
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Growth Arrest ◽  
Specific Inhibitor ◽  
Time Frame ◽  
Cycle Progression ◽  
Dependent Growth ◽  
Rate Limiting

The polyamines spermidine and spermine and their precursor, putrescine, are required for the growth and proliferation of eukaryotic cells. This study compares and contrasts growth arrest caused by polyamine depletion in the untransformed IEC-6 cell line with that in the p53-mutated colon cancer Caco-2 cell line. Cells were grown in the presence or absence of α-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, the first rate-limiting enzyme in the synthesis of polyamines. Depletion of polyamines inhibited the growth of both cell lines equally and over the same time frame. However, whereas IEC-6 cells were arrested in the G1 phase of the cell cycle, there was no accumulation of Caco-2 cells in any particular phase. In IEC-6 cells, growth arrest was accompanied by elevated levels of p53 and p21Waf1/Cip1 (p21). There were no changes in p53 levels in Caco-2 cells. Levels of p21 increased in Caco-2 cells on day 2 without any effect on cell cycle progression. The amount of cyclin-dependent kinase (Cdk)2 protein was unchanged by polyamine depletion in both cell lines. However, the activity of Cdk2 was significantly inhibited by DFMO in IEC-6 cells. These data suggest that in the untransformed IEC-6 cells the regulation of Cdk2 activity and progression through the cell cycle are p53- and p21 dependent. Growth arrest in the p53-mutated Caco-2 line after polyamine depletion occurs by a different, yet unknown, mechanism.

scholarly journals Interleukin-2 expression in human carcinoma cell lines and its role in cell cycle progression

Oncogene ◽  
2000 ◽  
Vol 19 (4) ◽  
pp. 514-525 ◽  
Author(s):  
Torsten E Reichert ◽  
Shigeki Nagashima ◽  
Yoshiro Kashii ◽  
Joanna Stanson ◽  
Gui Gao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Carcinoma Cell ◽  
Interleukin 2 ◽  
Cycle Progression ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Human Carcinoma Cell

scholarly journals Induction of cell cycle progression by adenovirus E1A gene 13S- and 12S-mRNA products in quiescent rat cells.

1987 ◽  
Vol 7 (10) ◽  
pp. 3846-3852 ◽  
Author(s):  
T Nakajima ◽  
M Masuda-Murata ◽  
E Hara ◽  
K Oda
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Adenovirus Type ◽  
Inducible Promoter ◽  
Similar Rate ◽  
Cycle Progression ◽  
Adenovirus E1a ◽  
Tumor Virus ◽  
E1a Gene

Rat 3Y1 cell lines that express either adenovirus type 12 E1A 13S mRNA or 12S mRNA in response to dexamethasone treatment were established by introduction of recombinant vector DNA containing the E1A 13S- or 12S-mRNA cDNA placed downstream of the hormone-inducible promoter of mouse mammary tumor virus. These cell lines were growth arrested, and the induction of cell cycle progression was analyzed by flow cytometry after switch on of the cDNA by the addition of dexamethasone. The results indicate that the 13S- or 12S-mRNA product alone has the ability to cause progression of the cell cycle at a similar rate. The simultaneous addition of epidermal growth factor accelerated the rate of cell cycle progression in the transition from the G0/G1 phase to the S phase.

scholarly journals Microarray gene expression profiling in colorectal (HCT116) and hepatocellular (HepG2) carcinoma cell lines treated withMelicope ptelefolialeaf extract reveals transcriptome profiles exhibiting anticancer activity

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5203 ◽  
Author(s):  
Mohammad Faujul Kabir ◽  
Johari Mohd Ali ◽  
Onn Haji Hashim
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Replication ◽  
Cell Lines ◽  
Microarray Data ◽  
Expression Profiling ◽  
Cell Cycle Progression ◽  
Anticancer Activities ◽  
Microarray Gene Expression ◽  
Cycle Progression

BackgroundWe have previously reported anticancer activities ofMelicope ptelefolia(MP) leaf extracts on four different cancer cell lines. However, the underlying mechanisms of actions have yet to be deciphered. In the present study, the anticancer activity of MP hexane extract (MP-HX) on colorectal (HCT116) and hepatocellular carcinoma (HepG2) cell lines was characterized through microarray gene expression profiling.MethodsHCT116 and HepG2 cells were treated with MP-HX for 24 hr. Total RNA was extracted from the cells and used for transcriptome profiling using Applied Biosystem GeneChip™ Human Gene 2.0 ST Array. Gene expression data was analysed using an Applied Biosystems Expression Console and Transcriptome Analysis Console software. Pathway enrichment analyses was performed using Ingenuity Pathway Analysis (IPA) software. The microarray data was validated by profiling the expression of 17 genes through quantitative reverse transcription PCR (RT-qPCR).ResultsMP-HX induced differential expression of 1,290 and 1,325 genes in HCT116 and HepG2 cells, respectively (microarray data fold change, MA_FC ≥ ±2.0). The direction of gene expression change for the 17 genes assayed through RT-qPCR agree with the microarray data. In both cell lines, MP-HX modulated the expression of many genes in directions that support antiproliferative activity. IPA software analyses revealed MP-HX modulated canonical pathways, networks and biological processes that are associated with cell cycle, DNA replication, cellular growth and cell proliferation. In both cell lines, upregulation of genes which promote apoptosis, cell cycle arrest and growth inhibition were observed, while genes that are typically overexpressed in diverse human cancers or those that promoted cell cycle progression, DNA replication and cellular proliferation were downregulated. Some of the genes upregulated by MP-HX include pro-apoptotic genes (DDIT3, BBC3, JUN), cell cycle arresting (CDKN1A, CDKN2B), growth arrest/repair (TP53, GADD45A) and metastasis suppression (NDRG1). MP-HX downregulated the expression of genes that could promote anti-apoptotic effect, cell cycle progression, tumor development and progression, which include BIRC5, CCNA2, CCNB1, CCNB2, CCNE2, CDK1/2/6, GINS2, HELLS, MCM2/10 PLK1, RRM2 and SKP2. It is interesting to note that all six top-ranked genes proposed to be cancer-associated (PLK1, MCM2, MCM3, MCM7, MCM10 and SKP2) were downregulated by MP-HX in both cell lines.DiscussionThe present study showed that the anticancer activities of MP-HX are exerted through its actions on genes regulating apoptosis, cell proliferation, DNA replication and cell cycle progression. These findings further project the potential use of MP as a nutraceutical agent for cancer therapeutics.

scholarly journals High Mobility Group A1 Chromatin Regulators Function As Critical Drivers of Leukemogenesis in Preclinical Models of Relapsed, Pediatric B-Cell ALL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3946-3946
Author(s):  
Liping Li ◽  
Katharina Hayer ◽  
Lingling Xian ◽  
Li Luo ◽  
Leslie Cope ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
High Mobility ◽  
Transcriptional Networks ◽  
Rna Seq ◽  
Cycle Progression ◽  
Short Hairpin ◽  
Reh Cells

Introduction: Acute B-cell lymphoblastic leukemia (B-ALL) is the most common form of childhood leukemia and the leading cause of death in children with cancer. While therapy is often curative, about 10-15% of children will relapse with recurrent disease and abysmal outcomes. Actionable mechanisms that mediate relapse remain largely unknown. The gene encoding the High Mobility Group A1(HMGA1) chromatin regulator is overexpressed in diverse malignancies where high levels portend poor outcomes. In murine models, we discovered thatHmga1 overexpression is sufficient for clonal expansion and progression to aggressive acute lymphoid leukemia (Cancer Res 2008,68:10121, 2018,78:1890; Nature Comm 2017,8:15008). Further, HMGA1 is overexpressed in pediatric B-ALL (pB-ALL) blasts with highest levels in children who relapse early compared to those who achieve chronic remissions. Together, these findings suggest that HMGA1 is required for leukemogenesis and may foster relapse in B-ALL. We therefore sought to: 1) test the hypothesis that HMGA1 is a key epigenetic regulator required for leukemogenesis and relapse in pB-ALL, and, 2) elucidate targetable mechanisms mediated by HMGA1 in leukemogenesis. Methods: We silenced HMGA1 via lentiviral delivery of short hairpin RNAs targeting 2 different sequences in cell lines derived from relapsed pB-ALL (REH, 697). REH cells harbor the TEL-AML1 fusion; 697 cells express BCL2, BCL3, and cMYC. Next, we assessed leukemogenic phenotypes in vitro (proliferation, cell cycle progression, apoptosis, and clonogenicity) and leukemogenesis invivo. To dissect molecular mechanisms underlying HMGA1, we performed RNA-Seq and applied in silico pathway analysis. Results: There is abundant HMGA1 mRNA and protein in both pB-ALL cell lines and HMGA1 was effectively silenced by short hairpin RNA. Further, silencing HMGA1 dramatically halts proliferation in both cell lines, leading to a decrease in cells in S phase with a concurrent increase in G0/S1. Apoptosis also increased by 5-10% after HMGA1 silencing based on flow cytometry for Annexin V. In colony forming assays, silencing HMGA1 impaired clonogenicity in both pB-ALL cell lines. To assess HMGA1 function in leukemogenesis in vivo, we implanted control pB-ALL cells (transduced with control lentivirus) or those with HMGA1 silencing via tail vein injection into immunosuppressed mice (NOD/SCID/IL2 receptor γ). All mice receiving control REH cells succumbed to leukemia with a median survival of only 29 days. At the time of death, mice had marked splenomegaly along with leukemic cells circulating in the peripheral blood and infiltrating both the spleen and bone marrow. In contrast, mice injected with REH cells with HMGA1 silencing survived for >40 days (P<0.001) and had a significant decrease in tumor burden in the peripheral blood, spleen, and bone marrow. Similar results were obtained with 697 cells, although this model was more fulminant with control mice surviving for a median of only 17 days. To determine whether the leukemic blasts found in mice injected with ALL cells after HMGA1 silencing represented a clone that expanded because it escaped HMGA1 silencing, we assessed HMGA1 levels and found that cells capable of establishing leukemia had high HMGA1 expression, with levels similar to those observed in control cells without HMGA1 silencing. RNA-Seq analyses from REH and 697 cell lines with and without HMGA1 silencing revealed that HMGA1 up-regulates transcriptional networks involved in RAS/MAPK/ERK signaling while repressing the IDH1 metabolic gene, the latter of which functions in DNA and histone methylation. Studies are currently underway to identify effective agents to target HMGA1 pathways. Conclusions: Silencing HMGA1 dramatically disrupts leukemogenic phenotypes in vitro and prevents the development of leukemia in mice. Mechanistically, RNA-Seq analyses revealed that HMGA amplifies transcriptional networks involved cell cycle progression and epigenetic modifications. Our findings highlight the critical role for HMGA1 as a molecular switch required for leukemic transformation in pB-ALL and a rational therapeutic target that may be particularly relevant for relapsed B-ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of Piceatannol on Cell Cycle Progression in Prostate Cancer Cells (P05-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Larissa Kido ◽  
Eun-Ryeong Hahm ◽  
Valeria Cagnon ◽  
Mário Maróstica ◽  
Shivendra Singh
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cell Cycle Distribution ◽  
Mutant P53 ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Objectives Piceatannol (PIC) is a polyphenolic and resveratrol analog that is found in many vegetables consumed by humans. Like resveratrol, PIC has beneficial effects on health due to its anti-inflammatory, anti-oxidative and anti-proliferative features. However, the molecular targets of PIC in prostate cancer (PCa), which is the second most common cancer in men worldwide, are still poorly understood. Preventing cancer through dietary sources is a promising strategy to control diseases. Therefore, the aim of present study was to investigate the molecular mechanistic of actions of PIC in PCa cell lines with different genetic background common to human prostate cancer. Methods Human PCa cell lines (PC-3, 22Rv1, LNCaP, and VCaP) were treated with different doses of PIC (5–40 µM) and used for cell viability assay, measurement of total free fatty acids (FFA) and lactate, and cell cycle distribution. Results PIC treatment dose- and time-dependently reduced viability in PC-3 (androgen-independent, PTEN null, p53 null) and VCaP cells (androgen-responsive, wild-type PTEN, mutant p53). Because metabolic alterations, such as increased glucose and lipid metabolism are implicated in pathogenesis of in PCa, we tested if PIC could affect these pathways. Results from lactate and total free fatty acid assays in VCaP, 22Rv1 (castration-resistant, wild-type PTEN, mutant p53), and LNCaP (androgen-responsive, PTEN null, wild-type p53) revealed no effect of PIC on these metabolisms. However, PIC treatment delayed cell cycle progression in G0/G1 phase concomitant with the induction of apoptosis in both LNCaP and 22Rv1 cells, suggesting that growth inhibitory effect of PIC in PCa is associated with cell cycle arrest and apoptotic cell death at least LNCaP and 22Rv1 cells. Conclusions While PIC treatment does not alter lipid or glucose metabolism, cell cycle arrest and apoptosis induction are likely important in anti-cancer effects of PIC. Funding Sources São Paulo Research Foundation (2018/09793-7).

scholarly journals Anticancer Activity of Cynomorium coccineum

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 354 ◽  
Author(s):  
Mouna Sdiri ◽  
Xiangmin Li ◽  
William Du ◽  
Safia El-Bok ◽  
Yi-Zhen Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Cycle Progression

The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are unclear. To understand the potential anticancer activity, we screened Cynomorium coccineum and Cynomorium songaricum using three different extracts of each species. In this study, the selected extracts were evaluated for their ability to decrease survival rates of five different cancer cell lines. We compared the cytotoxicity of the three different extracts to the anticancer drug vinblastine and one of the most well-known medicinal mushrooms Amaurederma rude. We found that the water and alcohol extracts of C. coccineum at the very low concentrations possessed very high capacity in decreasing the cancer cells viability with a potential inhibition of tumorigenesis. Based on these primitive data, we subsequently tested the ethanol and the water extracts of C. coccineum, respectively in in vitro and in vivo assays. Cell cycle progression and induction of programmed cell death were investigated at both biological and molecular levels to understand the mechanism of the antitumor inhibitory action of the C. coccineum. The in vitro experiments showed that the treated cancer cells formed fewer and smaller colonies than the untreated cells. Cell cycle progression was inhibited, and the ethanol extract of C. coccineum at a low concentration induced accumulation of cells in the G1 phase. We also found that the C. coccineum’s extracts suppressed viability of two murine cancer cell lines. In the in vivo experiments, we injected mice with murine cancer cell line B16, followed by peritoneal injection of the water extract. The treatment prolonged mouse survival significantly. The tumors grew at a slower rate than the control. Down-regulation of c-myc expression appeared to be associated with these effects. Further investigation showed that treatment with C. coccineum induced the overexpression of the tumor suppressor Foxo3 and other molecules involved in inducing autophagy. These results showed that the C. coccineum extract exerts its antiproliferative activity through the induction of cell death pathway. Thus, the Cynomorium plants appear to be a promising source of new antineoplastic compounds.

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