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Journal of the National Cancer Institute Jun 2010Activated AKT is a marker of decreased event-free or overall survival in neuroblastoma (NB) patients. The aim of this study was to investigate the effect of perifosine,...
BACKGROUND
Activated AKT is a marker of decreased event-free or overall survival in neuroblastoma (NB) patients. The aim of this study was to investigate the effect of perifosine, a nontoxic AKT inhibitor, as a single agent on NB cell growth in vitro and in vivo.
METHODS
Four human NB cell lines (AS, NGP, BE2, and KCNR) were treated with increasing concentrations of perifosine, and a quantitative analysis of cell death (apoptosis) was performed by using MTS and caspase-3/7 activity assays. Survival of mice carrying xenograft NB tumors that were treated with perifosine (n = 6-7 mice per group) was compared with that of untreated mice (n = 7 mice per group) using Kaplan-Meier analysis. Tumor volumes were calculated to determine the effect of perifosine on NB tumor growth. Phosphorylation of AKT and expression of cleaved caspase-3 were measured in proteins from the tumors. All statistical tests were two-sided.
RESULTS
Perifosine, at 30 muM concentration, decreased AKT phosphorylation and increased apoptosis in all four NB cell lines in vitro. Perifosine-treated mice bearing xenograft NB tumors had longer survival than untreated mice (untreated vs treated, median survival: AS, 13 days, 95% confidence interval [CI] = 11 to 16 days vs not reached, P = .003; NGP, 22 days, 95% CI = 20 to 26 days vs not reached, P = .013; BE2, 24 days, 95% CI = 21 to 27 days vs not reached, P < .001; and KCNR, 18 days, 95% CI = 18 to 21 days vs not reached, P < .001). Perifosine treatment induced regression in AS tumors, growth inhibition in BE2 tumors, and slower growth in NGP and KCNR tumors. Inhibition of AKT phosphorylation and induction of caspase-dependent apoptosis were noted in tumors of perifosine-treated mice in all four in vivo NB tumor models.
CONCLUSIONS
Perifosine inhibited the activation of AKT and was an effective cytotoxic agent in NB cells in vitro and in vivo. Our study supports the future clinical evaluation of perifosine for the treatment of NB tumors.
Topics: Analysis of Variance; Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Clinical Trials as Topic; Disease Models, Animal; Growth Inhibitors; Humans; In Vitro Techniques; Kaplan-Meier Estimate; Luciferases; Luminescent Agents; Mice; Mutation; NIH 3T3 Cells; Neuroblastoma; Phosphorylation; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Transplantation, Heterologous
PubMed: 20463309
DOI: 10.1093/jnci/djq125 -
Mutation Research Dec 1988It is obvious that the simplest approach to cancer prevention is to avoid exposure to causative agents, whether they be tumor initiators, promoters, or agents that... (Review)
Review
It is obvious that the simplest approach to cancer prevention is to avoid exposure to causative agents, whether they be tumor initiators, promoters, or agents that enhance the progression of cells to increasing degrees of malignancy. On the other hand, this simple approach will not always be feasible, either because the causative agent cannot be readily removed from the environment, the precise agent is not known with certainty, or individuals have already suffered significant exposure. It is necessary, therefore, to develop new strategies that can arrest or even reverse tumor development at various stages in the carcinogenic process. The long latency in tumor development, the multistage nature of the process, and the potential reversibility of some of these stages, offer reasons for optimism that this can be achieved. Advances in our understanding of the fundamental mechanisms by which environmental agents produce disturbances in growth control suggest very specific strategies. This paper provides examples of how recent knowledge in the areas of growth factors, growth factor receptors, protein kinases, signal transduction pathways, oncogenes and growth suppressor genes might lead to the development of such strategies. Major problems will include the development of agents which will specifically act on the target cells of interest without producing toxicity to other tissues, as well as better methods for identifying those individuals who are at risk of developing cancer and, therefore, warrant such therapy.
Topics: Animals; Growth Inhibitors; Growth Substances; Humans; Models, Theoretical; Neoplasms; Signal Transduction; Suppression, Genetic
PubMed: 3057370
DOI: 10.1016/0027-5107(88)90202-3 -
Biomolecules Nov 2019Murici ( (L.) Kunth and (L.) DC.) and tapereba () are Amazonian fruits that contain bioactive compounds. Biochemical and molecular characterization of these fruits can...
Murici ( (L.) Kunth and (L.) DC.) and tapereba () are Amazonian fruits that contain bioactive compounds. Biochemical and molecular characterization of these fruits can reveal their potential use in preventing diseases, including cancer. The extracts were characterized regarding the presence and profile of carotenoids by high-performance liquid chromatography (HPLC), total phenolic content by the Folin-Ciocalteu assay, and antioxidant activity by antioxidant value 2,2-diphenyl-1-picrylhydrazyl (DPPH) content analysis, 22,20-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) content analysis, Ferric-Reducing Ability of Plasma (FRAP), and Oxygen Radical Absorbance Capacity (ORAC) analysis. The extracts of tapereba and murici studied were important sources of total carotenoids and lutein, respectively. The extracts were then tested for their effect on the viability of the A2780 ovarian cancer (OC) cell line and its cisplatin (CDDP)-resistant derived cell line, called ACRP, by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. Their influence on cell cycle and apoptosis were analyzed by using flow cytometry. Murici and tapereba cell extracts exhibited a strong bioactivity by inhibiting A2780 and ACRP cell viability by 76.37% and 78.37%, respectively, besides modulating the cell cycle and inducing apoptotic cell death. Our results open new perspectives for the development of innovative therapeutic strategies using these Amazon fruit extracts to sensitize ovarian cancer cells to current chemotherapeutic options.
Topics: Anacardiaceae; Apoptosis; Brazil; Cell Cycle; Cell Line, Tumor; Female; Fruit; Growth Inhibitors; Humans; Malpighiaceae; Ovarian Neoplasms; Plant Extracts
PubMed: 31698710
DOI: 10.3390/biom9110707 -
Journal of Biochemistry Sep 1991It was previously found that rabbit serum contains a growth-inhibitory substance for a tumorigenic rat liver cell line RSV-BRL. In the present study, the growth...
It was previously found that rabbit serum contains a growth-inhibitory substance for a tumorigenic rat liver cell line RSV-BRL. In the present study, the growth inhibitor was purified from normal rabbit serum to show a homogeneous protein band with a molecular weight (Mr) of 56 k on SDS-polyacrylamide gel electrophoresis under non-reducing conditions. The purified growth inhibitor, tentatively named rabbit serum-derived growth inhibitor (RSGI), potently inhibited the growth of RSV-BRL and nine kinds of other cell lines including three human tumor cell lines at a concentration of 20 ng/ml or higher. The growth-inhibitory effect of RSGI was reversible and appeared to be cytostatic rather than cytotoxic. RSGI was stable to heating at 56 degrees C for 30 min or treatment with 0.1 M 2-mercaptoethanol, but labile to heating at 100 degrees C for 3 min or treatment with 1 M acetic acid (pH 2.3), 6 M urea, 50% (v/v) 1-propanol, or 0.1% (w/v) trypsin. These properties of RSGI suggested that it was different from type beta transforming growth factors, tumor necrosis factor-alpha, and other known growth-regulatory factors.
Topics: Animals; Cell Division; Cell Line; Chromatography; Chromatography, Gel; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Culture Media; Growth Inhibitors; Hydrogen Bonding; Molecular Weight; Rabbits; Rats
PubMed: 1769970
DOI: 10.1093/oxfordjournals.jbchem.a123597 -
The Prostate May 2013In prostate cancer cells, transforming growth factor β (TGFβ) inhibits proliferation in earlier stages of the disease; however, the cancer cells become refractory to...
BACKGROUND
In prostate cancer cells, transforming growth factor β (TGFβ) inhibits proliferation in earlier stages of the disease; however, the cancer cells become refractory to growth inhibitory effects in advanced stages where TGFβ promotes cancer progression and metastasis. Inhibitor of differentiation (Id) family of closely related proteins (Id1-Id4) are dominant negative regulators and basic helix loop helix (bHLH) transcription factors and in general promote proliferation, and inhibit differentiation. In the present study, we have investigated the role of Id1 and Id3 proteins in the growth inhibitory effects of TGFβ on prostate cancer cells.
METHODS
The effect of TGF β on proliferation and Id1 and Id3 expression were investigated in PZ-HPV7, DU145, and PC3 cells. Id1 silencing through siRNA was also used in DU145 and PC3 cells to examine its role in anti-proliferative and migratory effects of TGFβ.
RESULTS
TGFβ increased expression of Id1 and Id3 in all cell lines followed by a later down regulation of Id1 in PZ-HPV7 expression and DU145 cells but not in PC3 cells. Id3 expression remained elevated in all three cell lines. This loss of Id1 protein correlated with an increase of CDKNI p21. Id1 knockdown in both DU145 and PC3 cells resulted in decreased proliferation. However, while TGFβ caused a further decrease in proliferation of DU145, but had no further effects in PC3 cells. Knockdown of Id1 or Id3 inhibited TGFβ1induced migration in PC3 cells.
CONCLUSIONS
These findings suggest an essential role of Id1 and Id3 in TGFβ1 effects on proliferation and migration in prostate cancer cells.
Topics: Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial Cells; Gene Expression Regulation, Neoplastic; Growth Inhibitors; Humans; Inhibitor of Differentiation Protein 1; Inhibitor of Differentiation Proteins; Male; Neoplasm Proteins; Prostatic Neoplasms; RNA, Small Interfering; Transforming Growth Factor beta1
PubMed: 23060149
DOI: 10.1002/pros.22603 -
Journal of Food Protection Jun 2019Small molecules (SMs) 1, 3, 4, and 5 are novel growth inhibitors of . These SMs are not toxic to tomato plant tissues including fruits. Combining biocontrol agents and...
Small molecules (SMs) 1, 3, 4, and 5 are novel growth inhibitors of . These SMs are not toxic to tomato plant tissues including fruits. Combining biocontrol agents and SMs enhanced the control of in infected plants. These SMs may be safe bactericides against and phytopathogens in produce.
Topics: Anti-Bacterial Agents; Benzylamines; Growth Inhibitors; Imidazoles; Solanum lycopersicum; Plant Structures; Salmonella enterica
PubMed: 31121102
DOI: 10.4315/0362-028X.JFP-18-555 -
Genes & Development Dec 2000Classical embryology has provided a clear view of the timing and hormonal cues that govern sexual differentiation. Molecular biology has added important details to this... (Review)
Review
Classical embryology has provided a clear view of the timing and hormonal cues that govern sexual differentiation. Molecular biology has added important details to this picture. The cloning of SRY, MIS, and INSL3 provide insight into the molecular signals that provide important cues at the cellular level. Continued understanding of these pathways may provide the necessary information to one day reverse defects of sexual differentiation.
Topics: Animals; Anti-Mullerian Hormone; Estrogens; Fertility; Genitalia, Male; Glycoproteins; Growth Inhibitors; Hormones; Humans; Insulin; Male; Proteins; Sex Differentiation; Testicular Hormones
PubMed: 11124800
DOI: 10.1101/gad.843800 -
Current Opinion in Genetics &... Oct 1999The mechanisms by which tissue size is controlled are poorly understood. Over 30 years ago, Bullough proposed the existence of chalones, which act as tissue-specific... (Review)
Review
The mechanisms by which tissue size is controlled are poorly understood. Over 30 years ago, Bullough proposed the existence of chalones, which act as tissue-specific negative growth regulators. The recent discovery of myostatin suggests that negative regulation of tissue growth may be an important mechanism for controlling skeletal muscle mass and raises the possibility that growth inhibitors may also be involved in regulating the size of other tissues.
Topics: Animals; Bone Morphogenetic Proteins; Growth Differentiation Factors; Growth Inhibitors; Mice; Muscle, Skeletal; Myostatin; Organ Size; Transforming Growth Factor beta
PubMed: 10508689
DOI: 10.1016/s0959-437x(99)00004-0 -
PLoS Computational Biology Nov 2021Advances in genetic engineering technologies have allowed the construction of artificial genetic circuits, which have been used to generate spatial patterns of...
Advances in genetic engineering technologies have allowed the construction of artificial genetic circuits, which have been used to generate spatial patterns of differential gene expression. However, the question of how cells can be programmed, and how complex the rules need to be, to achieve a desired tissue morphology has received less attention. Here, we address these questions by developing a mathematical model to study how cells can collectively grow into clusters with different structural morphologies by secreting diffusible signals that can influence cellular growth rates. We formulate how growth regulators can be used to control the formation of cellular protrusions and how the range of achievable structures scales with the number of distinct signals. We show that a single growth inhibitor is insufficient for the formation of multiple protrusions but may be achieved with multiple growth inhibitors, and that other types of signals can regulate the shape of protrusion tips. These examples illustrate how our approach could potentially be used to guide the design of regulatory circuits for achieving a desired target structure.
Topics: Animals; Cell Aggregation; Cell Communication; Cell Proliferation; Cell Shape; Cell Surface Extensions; Cellular Reprogramming Techniques; Computational Biology; Computer Simulation; Gene Regulatory Networks; Genetic Engineering; Growth Inhibitors; Humans; Models, Biological; Morphogenesis; Synthetic Biology
PubMed: 34748539
DOI: 10.1371/journal.pcbi.1009576 -
Proceedings of the National Academy of... Aug 1986Growth inhibitor/type beta transforming growth factor purified from BSC-1 cells and human platelets is shown to strongly inhibit the proliferation of Con A-stimulated...
Growth inhibitor/type beta transforming growth factor purified from BSC-1 cells and human platelets is shown to strongly inhibit the proliferation of Con A-stimulated mouse thymocytes. The inhibition can be achieved with growth inhibitor/type beta transforming growth factor concentrations approximately equal to 1/10th those necessary to inhibit keratinocyte cultures. The inhibitory effect in thymocyte cultures can be reversed by the addition of interleukin 2. These findings suggest that growth inhibitor/type beta transforming growth factor is a naturally occurring immunoregulator.
Topics: Animals; Cell Line; Chlorocebus aethiops; Growth Inhibitors; Interleukin-2; Lymphocyte Activation; Lymphocytes; Mice; Peptides; Skin; Transforming Growth Factors
PubMed: 3488549
DOI: 10.1073/pnas.83.15.5531