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Results for “Proliferation”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,459 records · Page 81
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Anchorage of curcumin onto PVP enhances anti-tumor effect of curcumin

Curcumin, a natural polyphenol compound, exhibits wide range of pharmacological activities. However, its poor aqueous solubility, weak stability, and rapid metabolism limit its potential development. In this study, solid dispersion of curcumin with PVP was developed. This study aimed to evaluate the loading capacity, stability, solubility, and anti-tumor activity of PVP-Cur solid dispersion. Scanning electron microscope (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and fourier transform infrared (FTIR) spectroscopy were used to investigate physical characterization of PVP-Cur. Loading capacity, stability, and solubility of PVP-Cur were evaluated by spectrophotometer. The biological effects of PVP-Cur on tumor cell proliferation and apoptosis were analyzed using CCK-8 assay and 7-AAD/AnnexinV-APC assay, respectively. PVP-cur-induced activation of caspase-3 and caspase-9 were evaluated by in vitro caspase activity assay and western blotting. It was interesting to note that PVP: curcumin in the ratios of 6:1 or 8:1 exhibited the highest loading capacity. Anchorage of curcumin onto PVP increased its solubility and stability. Compared with curcumin alone, PVP-Cur displayed an increased ability in abrogating tumor cell proliferation and inducing tumor cell apoptosis via mitochondria signaling, which was attributed by the enhanced cellular uptake of PVP-Cur. Anchorage of curcumin onto PVP was an effective way to increase the solubility and stability of curcumin. PVP-Cur increased anti-tumor ability and cellular uptake relative to curcumin, indicating that PVP-Cur is a promising candidate for anti-cancer drug development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Synthesis of novel α-aminophosphonates under microwave irradiation, biological evaluation as antiproliferative agents and apoptosis inducers

The synthesis of two series of α-aminophosphonates was achieved by Microwave Irradiation (MW), using the one-pot Kabachnik–Fields reaction. Based on a green chemistry approach, the reactions were carried out using ethanol as the only solvent and without any catalyst, and short reaction times (20–40 min), in variable yields. Both series were tested to determine their cell proliferation inhibition activity in MDA-MB-231, MCF-7 and MCF-10A cell lines. Ethyl 4-(((diphenoxyphosphoryl)(4-(diphenylamino)phenyl)methyl)amino) benzoate 4e and diphenyl (((4-(((S)-2-hydroxy-1-phenylethyl)carbamoyl)phenyl)amino)(4-hydroxyphenyl)methyl)phosphonate 6b, showed cell proliferation inhibition activity only in the cancer cell line MCF-7 and no effect on the normal cell line MFC-10A, both compounds caused cell death by inducing apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Screening for anticancer properties of thiazolidinedione compounds in a galactose media metastatic breast cancer cell model

The metastatic tumors of breast cancer lead to the mortality of patients in part due to the failure of chemotherapeutics to reach the brain and emergence of drug resistance. With the increase in drug resistance, we focused on targeting mitochondrial metabolism, which was recently found to be a viable and novel drug target in breast cancer. Here we screened several ligands for anticancer activity in a phenotypic screen using the MTT dye as a marker for cell proliferation. MCF-7 breast cancer cells were treated with compounds in the presence of galactose to ensure mitochondrial interaction by the compounds. The lead compound of our group, NL-1, a thiazolidinedione (TZD), was found to inhibit cell proliferation with an IC{sub 50} of 7.1 μM, whereas its unsaturated derivative CI-987 was more potent with a IC{sub 50} of 3.3 μM. The TZDs were affected by substitution on both the aromatic ring and the TZD warhead. Taken together, these compounds can serve as lead structures for mitochondrial targeted drug discovery programs in breast cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Toxicity of Doxorubicin on Pig Liver After Chemoembolization with Doxorubicin-loaded Microspheres: A Pilot DNA-microarrays and Histology Study

The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques.The left hepatic arteries of two pigs were embolized with 1 mL of doxorubicin-loaded (25 mg; (DoxMS)) or non-loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1 week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p < 0.01; fold-change > 2) between two groups were classified by biological process. At 1 week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 and 38 % of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up-regulated genes following embolization with DoxMS (vs. BlandMS, n = 353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down-regulated genes (n = 120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration. DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Effect of Polyethylene Terephthalate on Functional Properties of Endothelial and Mesenchymal Cells

We studied the influence of vascular prostheses made of polytetrafluoroethylene and polyethylene terephthalate on the proliferation, migration, and NO production by bone marrow mesenchymal stem cells, human endothelial progenitor cells, and EA.hy926 endothelial cells, colonization of the prosthesis surface by endothelial and mesenchymal cells was also analyzed. Synthetic prostheses have a negative effect on cell proliferation and migration, while surface treatment with proteins (fibronectin or gelatin) promotes colonization of the prostheses with cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Changes in the Metastatic Properties of MDA-MB-231 Cells after IGFBP6 Gene Knockdown Is Associated with Increased Expression of miRNA Genes Controlling INSR, IGF1R, and CCND1 Genes

Metastatic cascade is associated with the process of epithelial-mesenchymal transition accompanied by changes in cell proliferation, migration, adhesion, and invasiveness mediated by the insulin-like growth factor (IGF) signal pathway. IGFBP6 protein binds IGF and prevents its interaction with receptors. IGFBP6 gene knockdown through RNA-interference inhibits cell migration and increased the rate of proliferation of breast cancer MDA-MB-231 cells. IGFBP6 knockdown cells are characterized by increased expression of MIR100 and MIRLET7A2 genes encoding hsa-miR-100-3p, hsa-miR-100-5p, hsa-let-7a-5p, and hsa-let-7a-2-3p miRNA. The target genes of these microRNAs are IGF2, IGF1R, INSR, and CCND1 associated with IGF signaling pathway and proliferative and migratory activity during the metastatic cascade. A significant decrease in the expression of INSR and CCND1 genes was demonstrated by PCR and microarray analysis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Regulation of Proliferative Processes in Rat Adrenal Cortex by Transcriptional Factor PRH under Conditions of Developmental Exposure to Endocrine Disruptor DDT

The effects of endocrine disrupters of transcriptional control of morphogenesis are poorly studied. Changes in the expression of transcriptional factor PRH and proliferation of adrenal cortical cells were analyzed in pubertal and postpubertal rats exposed prenatally and postnatally to low doses of endocrine disrupter DDT. In rats exposed to DDT, the expression of PRH and proliferation of adrenal cortical cells differed from those in control rats. Association between these parameters was weakened in the zona glomerulosa and zona reticularis and was absent in the zona fasciculata. These findings suggest that exposure to DDT in pre- and postnatal periods impairs the regulation of proliferative processes by transcriptional factor PRH in all zones of rat adrenal cortex, which can be a mechanism of the disruptive action of DDT.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Evaluation of additive manufacturing side channels for nuclear nonproliferation applications

The nuclear industry is continuing to grow and adopt new technologies to manufacture components. One of the technologies under consideration is additive manufacturing (AM). AM could make production of components at lower cost and could lessen lead times significantly. However, AM could be prone to proliferation risks. AM machines give off signatures during the manufacturing process, and these signatures offer an alternative means of observing the component. Correlations between these signatures and the geometry being manufactured could be developed; enabling proliferators as they could take advantage of these correlations to steal AM manufacturing instructions relating to nuclear technology. This work pertains to preliminary work exploring the feasibility of tapping into AM side channels to predict geometries being manufactured on AM machines. The feasibility of utilizing vibration to draw geometric correlations will be assessed on an Ultimaker 2 + thermoplastic 3D printer.

Additive manufacturing↗
DOE OSTI2019

Fabrication and Cytocompatibility Evaluation of Psyllium Husk (Isabgol)/Gelatin Composite Scaffolds

Psyllium husk or isabgol contains xylan backbone linked with arabinose, rhamnose, and galacturonic acid units (arabinoxylans). In this study, we demonstrate the fabrication and characterization of a macroporous three-dimensional (3D) composite scaffold by mixing psyllium husk powder (PH) and gelatin (G) in different ratios, viz.100 PH, 75/25 PH/G, and 50/50 PH/G (w/w), using an EDC-NHS coupling reaction followed by freeze-drying method. The reaction was performed in aqueous as well as in alcoholic media to determine the most appropriate solvent system for this purpose. The mechanical strength of the scaffold system was improved from 151 to 438 kPa. The fabricated scaffolds exhibited enhanced structural stability, remarkable swelling capacity, and escalated cell growth and proliferation. ATR-FTIR analysis showed the presence of amide and ester bonds indicating covalent crosslinking. SEM micrographs revealed the porous nature of the scaffolds with pores ranging from 30 to 150 μm, and further pore size distribution curve indicated that 75/25 PH/G (w/w%) EDC-NHS-alcohol scaffold exhibited the best fit to the Gaussian distribution. Swelling capacity of the 100 PH EDC-NHS-alcohol scaffolds was found to be nearly 40% from its original weight in 48 h. MTT assay using fibroblast cells revealed ~ 80% cellular proliferation by 6th day within the fabricated scaffolds in comparison to control. .

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

IL-39 acts as a friend to pancreatic cancer

Pancreatic cancer is the most lethal digestive cancer and the fourth leading cause of cancer death in the US. IL-39, a heterodimer of p19 and EBI3, is a newly found cytokine and its role in the pathogenesis of neoplasia has not been studied yet. This study was designed to investigate the direct role of IL-39 in the growth of pancreatic cancer. Clonogenic survival assay, cell proliferation, and caspase-3 activity kits were used to evaluate the direct effects of IL-39 on cell survival, proliferation and apoptosis of the widely studied pancreatic cancer cell line MiaPaCa-2. We further investigated the possible molecular mechanisms by using RT-PCR and IHC. The percentage of colonies of pancreatic cancer cells increased significantly in the presence of IL-39. This was paralleled with the increase in the OD value of cancer cells in the presence of IL-39. Interestingly, the relative caspase-3 activity in cancer cells decreased significantly in the presence of IL-39. Furthermore, the pro-tumor effect of IL-39 on pancreatic cancer cells correlated with decreased anti-proliferative molecule p21.The anti-apoptotic effect of IL-39 correlated with decreased pro-apoptotic molecule TRAILR1. These results suggest that IL-39 favors growth of pancreatic cancer by promoting growth and inhibiting apoptosis of cancer cells. This suggests that IL-39 acts as a friend to pancreatic cancer. Thus, inhibition of effect of IL-39 on cells might be a promising strategy to treat pancreatic cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Identification of candidate diagnostic and prognostic biomarkers for human prostate cancer: RPL22L1 and RPS21

Prostate cancer (PCa) is one of the most common malignancies in men worldwide. This study was designed to investigate the potential of Ribosomal Protein L22-like1 (RPL22L1) and Ribosomal Protein S21 (RPS21) as diagnostic and prognostic biomarkers for PCa. First, RPL22L1 and RPS21 were screened as the key molecular of PCa by bioinformatics analysis. Subsequently, the prostate tissue samples were stained for antibodies against RPL22L1 and RPS21. The unbiased signal quantification was performed by ImageJ software, and the results showed that the expression of RPL22L1 and RPS21 exhibited significant differences between the PCa tissues and the normal prostate tissues. Receiver-operating characteristics (ROC) curves were prepared, and then the area under the curve (AUC) values of RPL22L1 and RPS21 were calculated as 0.798 and 0.768, and the likelihood ratio (LR) values of RPL22L1 and RPS21 were calculated as 2.86 and 2.53. These data implied that the over-expression of RPL22L1 and RPS21 is associated with the presence of PCa. The further analysis suggested that the expression of RPL22L1 and RPS21 were significantly higher in high Gleason grade than they were in low Gleason grade. In addition, in vitro studies were undertaken to evaluate the roles of RPL22L1 and RPS21 in PCa. The results revealed that these genes promote PCa cell proliferation, migration and invasion, and inhibit PCa cell apoptosis. Taken together, these data showed that RPL22L1 and RPS21 exhibited higher expression in human prostate cancer tissue, and involved in PCa cell proliferation and invasion. This research provided a novel insight into diagnostic and prognostic biomarkers for PCa.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Improved viability and activity of neutrophils differentiated from HL-60 cells by co-culture with adipose tissue-derived mesenchymal stem cells

Highlights: Black-Right-Pointing-Pointer Neutropenia is a principal complication of cancer treatment. Black-Right-Pointing-Pointer Co-culture of neutrophils with AD-MSC retained cell survival and proliferation and inhibited neutrophil apoptosis under serum starved conditions. Black-Right-Pointing-Pointer AD-MSC increased functions of neutrophil. Black-Right-Pointing-Pointer AD-MSC promoted the viability of neutrophils by enhancing respiratory burst through the expression of IFN-{alpha}, G-CSF, and TGF-{beta}. Black-Right-Pointing-Pointer AD-MSC can be used to improve immunity for neutropenia treatment. -- Abstract: Neutropenia is a principal complication of cancer treatment. We investigated the supportive effect of adipose tissue-derived mesenchymal stem cells (AD-MSCs) on the viability and function of neutrophils. Neutrophils were derived from HL-60 cells by dimethylformamide stimulation and cultured with or without AD-MSCs under serum-starved conditions to evaluate neutrophil survival, proliferation, and function. Serum starvation resulted in the apoptosis of neutrophils and decreased cell survival. The co-culture of neutrophils and AD-MSCs resulted in cell survival and inhibited neutrophil apoptosis under serum-starved conditions. The survival rate of neutrophils was prolonged up to 72 h, and the expression levels of interferon (IFN)-{alpha}, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)-{beta} in AD-MSCs were increased after co-culture with neutrophils. AD-MSCs promoted the viability of neutrophils by inhibiting apoptosis as well as enhancing respiratory burst, which could potentially be mediated by the increased expression of IFN-{alpha}, G-CSF, and TGF-{beta}. Thus, we conclude that the use of AD-MSCs may be a promising cell-based therapy for increasing immunity by accelerating neutrophil function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Effects of short-hairpin RNA-inhibited {beta}-catenin expression on the growth of human multiple myeloma cells in vitro and in vivo

Highlights: Black-Right-Pointing-Pointer {beta}-Catenin expression were markedly down-regulated by CTNNB1 shRNA. Black-Right-Pointing-Pointer CTNNB1 shRNA could inhibit the proliferation of RPMI8226 cells. Black-Right-Pointing-Pointer Significantly profound apoptotic cell death in CTNNB1 shRNA cells. Black-Right-Pointing-Pointer In vivo, CTNNB1 silence led to a growth inhibition of myeloma growth. Black-Right-Pointing-Pointer c-myc and {beta}-catenin in the expression cells of cleaved caspase-3 were increased. -- Abstract: Multiple myeloma (MM) is thrombogenic as a consequence of multiple hemostatic effects. Overexpression of {beta}-catenin has been observed in several types of malignant tumors, including MM. However, the relationship between {beta}-catenin expression and MM remains unclear. In the present study, RNA interference was used to inhibit {beta}-catenin expression in RPMI8226 cells. RT-PCR and Western blotting analyses showed that {beta}-catenin mRNA and protein expression were markedly down-regulated by CTNNB1 shRNA. Western blotting showed that the protein levels of cyclin D1 and glutamine synthetase were downregulated and supported the transcriptional regulatory function of {beta}-catenin. The MTT assay showed that CTNNB1 shRNA could have significant inhibitory effects on the proliferation of RPMI8226 cells. The TOPflash reporter assay demonstrated significant downregulation after CTNNB1 shRNA transfection in RPMI8226 cells. Flow cytometric analyses also showed significantly profound apoptosis in CTNNB1 shRNA cells. We found CTNNB1 silence led to growth inhibition of MM growth in vivo. Immunohistochemical analyses showed that c-myc and {beta}-catenin were reduced in CTNNB1 shRNA tumor tissues, but that expression of cleaved caspase-3 was increased. These results show that {beta}-catenin could be a new therapeutic agent that targets the biology of MM cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

Highlights: Black-Right-Pointing-Pointer cAMP blocks cell death induced by TNF and actinomycin D in cultured hepatocytes. Black-Right-Pointing-Pointer cAMP blocks NF-{kappa}B activation induced by TNF and actinomycin D. Black-Right-Pointing-Pointer cAMP blocks DISC formation following TNF and actinomycin D exposure. Black-Right-Pointing-Pointer cAMP blocks TNF signaling at a proximal step. -- Abstract: Tumor necrosis factor {alpha} (TNF) is a pleiotropic proinflammatory cytokine that plays a role in immunity and the control of cell proliferation, cell differentiation, and apoptosis. The pleiotropic nature of TNF is due to the formation of different signaling complexes upon the binding of TNF to its receptor, TNF receptor type 1 (TNFR1). TNF induces apoptosis in various mammalian cells when the cells are co-treated with a transcription inhibitor like actinomycin D (ActD). When TNFR1 is activated, it recruits an adaptor protein, TNF receptor-associated protein with death domain (TRADD), through its cytoplasmic death effector domain (DED). TRADD, in turn, recruits other signaling proteins, including TNF receptor-associated protein 2 (TRAF2) and receptor-associated protein kinase (RIPK) 1, to form a complex. Subsequently, this complex combines with FADD and procaspase-8, converts into a death-inducing signaling complex (DISC) to induce apoptosis. Cyclic AMP (cAMP) is a second messenger that regulates various cellular processes such as cell proliferation, gene expression, and apoptosis. cAMP analogues are reported to act as anti-apoptotic agents in various cell types, including hepatocytes. We found that a cAMP analogue, dibutyryl cAMP (db-cAMP), inhibits TNF + ActD-induced apoptosis in rat hepatocytes. The protein kinase A (PKA) inhibitor KT-5720 reverses this inhibitory effect of cAMP on apoptosis. Cytoprotection by cAMP involves down-regulation of various apoptotic signal regulators like TRADD and FADD and inhibition of caspase-8 and caspase-3 cleavage. We also found that cAMP exerts its affect at the proximal level of TNF signaling by inhibiting the formation of the DISC complex upon the binding of TNF to TNFR1. In conclusion, our study shows that cAMP prevents TNF + ActD-induced apoptosis in rat hepatocytes by inhibiting DISC complex formation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Enhanced accumulation of adipocytes in bone marrow stromal cells in the presence of increased extracellular and intracellular [Ca{sup 2+}]

Highlights: Black-Right-Pointing-Pointer High [Ca{sup 2+}]{sub o} enhances adipocyte accumulation in the presence of adipogenic inducers. Black-Right-Pointing-Pointer High [Ca{sup 2+}]{sub o} enhances both proliferation and adipocyte differentiation in BMSCs. Black-Right-Pointing-Pointer High [Ca{sup 2+}]{sub o} induces an increase in [Ca{sup 2+}]{sub o} in BMSCs. Black-Right-Pointing-Pointer An intracellular Ca{sup 2+} chelator suppresses the enhancement in adipocyte accumulation. Black-Right-Pointing-Pointer Controlling [Ca{sup 2+}]{sub o} may govern the balance of adipocyte and osteoblast development. -- Abstract: The bone marrow stroma contains osteoblasts and adipocytes that have a common precursor: the pluripotent mesenchymal stem cell found in bone marrow stromal cells (BMSCs). Local bone marrow Ca{sup 2+} levels can reach high concentrations due to bone resorption, which is one of the notable features of the bone marrow stroma. Here, we describe the effects of high [Ca{sup 2+}]{sub o} on the accumulation of adipocytes in the bone marrow stroma. Using primary mouse BMSCs, we evaluated the level of adipocyte accumulation by measuring Oil Red O staining and glycerol-3-phosphate dehydrogenase (GPDH) activity. High [Ca{sup 2+}]{sub o} enhanced the accumulation of adipocytes following treatment with both insulin and dexamethasone together but not in the absence of this treatment. This enhanced accumulation was the result of both the accelerated proliferation of BMSCs and their differentiation into adipocytes. Using the fura-2 method, we also showed that high [Ca{sup 2+}]{sub o} induces an increase in [Ca{sup 2+}]{sub i}. An intracellular Ca{sup 2+} chelator suppressed the enhancement in adipocyte accumulation due to increased [Ca{sup 2+}]{sub o} in BMSCs. These data suggest a new role for extracellular Ca{sup 2+} in the bone marrow stroma: increased [Ca{sup 2+}]{sub o} induces an increase in [Ca{sup 2+}]{sub i} levels, which in turn enhances the accumulation of adipocytes under certain conditions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Inhibition of NAMPT pathway by FK866 activates the function of p53 in HEK293T cells

Highlights: Black-Right-Pointing-Pointer In 293T cells, p53 is considered to be inactive due to its interaction with the large T-antigen. Black-Right-Pointing-Pointer Acetylation of p53 at lysine 382 is important for its functional activation. Black-Right-Pointing-Pointer First evidence to document the presence of a functional p53 in 293T cells. Black-Right-Pointing-Pointer Inhibition of NAMPT/SIRT pathway by FK866 in 293T cells increases the functional activity of p53. Black-Right-Pointing-Pointer This activation of p53 involves reversible acetylation of p53 at lysine 382. -- Abstract: Inactivation of p53 protein by endogenous and exogenous carcinogens is involved in the pathogenesis of different human malignancies. In cancer associated with SV-40 DNA tumor virus, p53 is considered to be non-functional mainly due to its interaction with the large T-antigen. Using the 293T cell line (HEK293 cells transformed with large T antigen) as a model, we provide evidence that p53 is one of the critical downstream targets involved in FK866-mediated killing of 293T cells. A reduced rate of apoptosis and an increased number of cells in S-phase was accompanied after knockdown of p53 in these cells. Inhibition of NAMPT by FK866, or inhibition of SIRT by nicotinamide decreased proliferation and triggered death of 293T cells involving the p53 acetylation pathway. Additionally, knockdown of p53 attenuated the effect of FK866 on cell proliferation, apoptosis, and cell cycle arrest. The data presented here shed light on two important facts: (1) that p53 in 293T cells is active in the presence of FK866, an inhibitor of NAMPT pathway; (2) the apoptosis induced by FK866 in 293T cells is associated with increased acetylation of p53 at Lys382, which is required for the functional activity of p53.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Triparanol suppresses human tumor growth in vitro and in vivo

Highlights: Black-Right-Pointing-Pointer Demonstrate Triparanol can block proliferation in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrate Triparanol can induce apoptosis in multiple cancer cells. Black-Right-Pointing-Pointer Proved Triparanol can inhibit Hedgehog signaling in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrated Triparanol can impede tumor growth in vivo in mouse xenograft model. -- Abstract: Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Involvement of the transcription factor FoxM1 in contact inhibition

Highlights: Black-Right-Pointing-Pointer The transcription factor FoxM1 is downregulated upon contact inhibition. Black-Right-Pointing-Pointer The decrease in FoxM1 levels occurs very likely due to inhibition of ERK activity. Black-Right-Pointing-Pointer The decrease in FoxM1 is not sufficient, but required for contact inhibition. Black-Right-Pointing-Pointer We propose a new model of contact inhibition involving pRB/E2F and FoxM1. -- Abstract: Contact inhibition is a crucial mechanism regulating proliferation in vitro and in vivo. Although it is generally accepted that contact inhibition plays a pivotal role in maintaining tissue homeostasis, the molecular mechanisms of contact inhibition are still not fully understood. FoxM1 is known as a proliferation-associated transcription factor and is upregulated in many cancer types. Vice versa, anti-proliferative signals, such as TGF-{beta} and differentiation signals decrease FoxM1 expression. Here we investigated the role of FoxM1 in contact inhibition in fibroblasts. We show that protein expression of FoxM1 is severely and rapidly downregulated upon contact inhibition, probably by inhibition of ERK activity, which then leads to decreased expression of cyclin A and polo-like kinase 1. Vice versa, ectopic expression of FoxM1 prevents the decrease in cyclin A and polo-like kinase 1 and causes a two-fold increase in saturation density indicating loss of contact inhibition. Hence, we show that downregulation of FoxM1 is required for contact inhibition by regulating expression of cyclin A and polo-like kinase 1.

60 APPLIED LIFE SCIENCES↗