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Antiproliferative Effects (antiproliferative + effects)

Distribution by Scientific Domains

Medical Sciences	58%
Chemistry	21%
Life Sciences	19%

Selected Abstracts

PAMAM Dendrimers Mediate siRNA Delivery to Target Hsp27 and Produce Potent Antiproliferative Effects on Prostate Cancer Cells

CHEMMEDCHEM, Issue 8 2009
Xiao-xuan Liu
Abstract RNA interference (RNAi) holds great promise for the treatment of inherited and acquired diseases, provided that safe and efficient delivery systems are available. Herein we report that structurally flexible triethanolamine (TEA) core PAMAM dendrimers are able to deliver an Hsp27 siRNA effectively into prostate cancer (PC-3) cells by forming stable nanoparticles with siRNA, protecting the siRNA nanoparticles from enzymatic degradation, and enhancing cellular uptake of siRNA. The Hsp27 siRNA resulted in potent and specific gene silencing of heat-shock protein,27, an attractive therapeutic target in castrate-resistant prostate cancer. Silencing of the hsp27 gene led to induction of caspase-3/7-dependent apoptosis and inhibition of PC-3 cell growth in,vitro. In addition, the siRNA,dendrimer complexes are non-cytotoxic under the conditions used for siRNA delivery. Altogether, TEA core PAMAM dendrimer-mediated siRNA delivery, in combination with RNAi that specifically targets Hsp27, may constitute a promising approach for combating castrate-resistant prostate cancer, for which there is no efficacious treatment. [source]

Antiproliferative effects of different plant parts of Panax notoginseng on SW480 human colorectal cancer cells

PHYTOTHERAPY RESEARCH, Issue 1 2009
Chong-Zhi Wang
Abstract The chemical constituents and antiproliferative effects on SW480 human colorectal cancer cells of different plant parts of P. notoginseng were evaluated. The contents of saponins in extracts from root, rhizome, flower and berry of P. notoginseng were determined using high performance liquid chromatography. The contents and proportions of saponins were different among the four plant parts. Using the cell counting method, the antiproliferative effects were evaluated and the results indicated all four extracts, at 0.05,1.0 mg/mL, showed concentration-related antiproliferative effects on the cancer cells. The flower extract had stronger effects compared with the other three extracts; at 1.0 mg/mL, it inhibited the cell growth by 93.1% (p < 0.01). The antiproliferative effects of major saponins in notoginseng, notoginsenoside R1, ginsenosides Rb1, Rb3 and Rg1, were also evaluated, and the observed effects of major constituents support the pharmacological activities of extracts. The effects of notoginseng extracts on cell cycle and apoptosis of SW480 cells were determined using flow cytometry. Notoginseng extract can arrest the cells in S and G2/M phases. Remarkably apoptosis induction activities of notoginseng extracts were observed with the flower extract possessing the most potent effect, supporting the antiproliferative effect. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Antimutagenic and antiproliferative effects of roasted and defatted peanut dregs on human leukemic U937 and HL-60 cells

PHYTOTHERAPY RESEARCH, Issue 3 2008
Jean-Yu Hwang
Abstract The antimutagenic effects on Salmonella typhimurium TA98 and TA100 strains and antiproliferative effects on leukemia cell lines (U937 and HL-60) of peanut protein isolate (PPI), peanut protein isolate enzyme hydrolysate (PPIEH), roasted and defatted peanut dregs (RDPD), and roasted and defatted peanut dregs enzyme hydrolysate (RDPDEH) were investigated. The antimutagenic effects on B(a)P and 4-NQO toward the TA98 and TA100 strains were found to follow a diminishing order: RDPD > RDPDEH >> PPI = PPIEH with dose-dependency. Antiproliferative effects on leukemia cells U937 and HL-60 were also detected. RDPD was found to be the most effective of all the peanut preparations. At 100 µg/mL concentration, RDPD inhibited the proliferation of U937 and HL-60 cells by 56% and 52%, respectively. We propose to consider RDPD and RDPDEH in the development of natural chemotherapeutic or chemopreventive dietary supplements against leukemia and to upgrade the utilization of these by-products in peanut oil production. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Relationship Between Anticancer Activity and Stereochemistry of Saldach Ligands and their Iron(III) Complexes

ARCHIV DER PHARMAZIE, Issue 11 2009
Annegret Hille
Abstract (R,R)-, (S,S)- and (R,S)- N,N,-bis(salicylidene)-1,2-diaminocyclohexane (saldach) and their iron(III) complexes were screened for anticancer activity against MCF-7 and MDA-MB 231 breast cancer as well as HT-29 colon carcinoma cells. Antiproliferative effects depended on the presence of the central atom iron but were independent on the configuration at the saldach ligand. While the free ligands were inactive, the iron(III) derivatives displayed anticancer activity within a concentration range of 1 to 5 ,M irrespective of the used cell line. At 5 ,M they were even more active than cis -platin. A mode of action comparable to cis -platin can be excluded because it is very likely that the DNA is not the primary target of [FeIII (saldach)] complexes. [source]

Antiproliferative effects of some N -benzylideneanilines

CELL BIOCHEMISTRY AND FUNCTION, Issue 1 2008
Yusuf Özkay
Abstract A series of Schiff bases including N -benzylideneaniline (NBA) nuclei were prepared. The chemical products obtained were characterized by mass spectometry (APCI), 1H NMR, and IR spectroscopy in order to seek their cytotoxic and proliferation effects on human small lung (A549) and cervical (HeLa) cancer cell lines with biochemical assays. All of the synthesized compounds showed antiproliferative effects to different extents. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Antiproliferative effects of essential oils and their major constituents in human renal adenocarcinoma and amelanotic melanoma cells

CELL PROLIFERATION, Issue 6 2008
M. R. Loizzo
Materials and methods: Essential oils were obtained by hydrodistillation and were analysed by gas chromatography and gas chromatography coupled to mass spectrometry. Antiproliferative activity was tested on amelanotic melanoma C32 cells and on renal cell adenocarcinoma cells, using the sulphorhodamine B assay. Results: Cupressus sempervirens ssp. pyramidalis leaf oil exerted the highest cytotoxic activity with an IC50 value of 104.90 µg/mL against C32, followed by activity of P. orientalis and P. asperula on the renal adenocarcinoma cell line (IC50 of 121.93 and 139.17 µg/mL, respectively). P. orientalis essential oil was also active against amelanotic melanoma with an IC50 of 330.04 µg/mL. Three identified terpenes, linalool, ,-caryophyllene and ,-cedrol, were found to be active on both cell lines tested. Conclusions: Our findings provide novel insights into the field of cytotoxic properties of essential oils. This study provided evidence on how cytotoxic activity of the oils is not always related to their major constituents, except for lower activity found in both cell lines for ,-cedrol. Interestingly, ,-caryophyllene and linalool exhibited comparable IC50 values to the commercial drug vinblastine on the ACHN cell line. This opens a new field of investigation to discover mechanisms responsible for the observed activity. [source]

Vanadium-induced apoptosis of HaCaT cells is mediated by c-fos and involves nuclear accumulation of clusterin

FEBS JOURNAL, Issue 14 2009
Soultana Markopoulou
Vanadium exerts a variety of biological effects, including antiproliferative responses through activation of the respective signaling pathways and the generation of reactive oxygen species. As epidermal cells are exposed to environmental insults, human keratinocytes (HaCaT) were used to investigate the mechanism of the antiproliferative effects of vanadyl(IV) sulfate (VOSO4). Treatment of HaCaT cells with VOSO4 inhibited proliferation and induced apoptosis in a dose-dependent manner. Inhibition of proliferation was associated with downregulation of cyclins D1 and E, E2F1, and the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p27Kip1. Induction of apoptosis correlated with upregulation of the c-fos oncoprotein, changes in the expression of clusterin (CLU), an altered ratio of antiapoptotic to proapoptotic Bcl-2 protein family members, and poly(ADP-ribose) polymerase-1 cleavage. Forced overexpression of c-fos induced apoptosis in HaCaT cells that correlated with secretory CLU downregulation and upregulation of nuclear CLU (nCLU), a pro-death protein. Overexpression of Bcl-2 protected HaCaT cells from vanadium-induced apoptosis, whereas secretory CLU overexpression offered no cytoprotection. In contrast, nCLU sensitized HaCaT cells to apoptosis. Our data suggest that vanadium-mediated apoptosis was promoted by c-fos, leading to alterations in CLU isoform processing and induction of the pro-death nCLU protein. [source]

Growth inhibition of orthotopic anaplastic thyroid carcinoma xenografts in nude mice by PTK787/ZK222584 and CPT-11

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 5 2006
Seungwon Kim MD
Abstract Background. A preclinical evaluation of CPT-1 (Camptosar, irinotecan) and PTK787/ZK222584, a vascular endothelial growth factor receptor (VEGFR-2) tyrosine kinase inhibitor, as therapeutic agents against anaplastic thyroid carcinoma (ATC) was performed in vitro and in an orthotopic model of ATC in nude mice. Methods. The cytotoxic and cytostatic effects of CPT-11 on ATC cell lines were evaluated. The antitumor effects of CPT-11 in combination with PTK787/ZK222584 on orthotopic ATC xenografts in nude mice were also studied. Results. CPT-11 demonstrated significant antiproliferative effects on ATC cell lines. In vivo, PTK787/ZK222584, CPT-11, and the two agents together produced 61%, 82%, and 89% decrease in tumor growth, respectively. The differences in tumor volume between CPT-11 and CPT-11 + PTK787/ZK222584 groups were not statistically significant. PTK787/ZK222584 inhibited the phosphorylation of VEGFR-2 on tumor endothelium and decrease the tumor microvessel density. Conclusions. The camptothecin class of chemotherapeutic agents and antiangiogenic agents such as PTK787/ZK222584 warrant further study as novel therapeutic agents against ATC. © 2005 Wiley Periodicals, Inc. Head Neck27: 389,399, 2006 [source]

Novel Sulfonamide Derivatives as Inhibitors of Histone Deacetylase

HELVETICA CHIMICA ACTA, Issue 7 2005

Inhibition of the enzyme histone deacetylase (HDAC) is emerging as a novel approach to the treatment of cancer. A series of novel sulfonamide derivatives were synthesized and evaluated for their ability to inhibit human HDAC. Compounds were identified which are potent enzyme inhibitors, with IC50 values in the low nanomolar range against enzyme obtained from HeLa cell extracts, and with antiproliferative effects in cell culture. Extensive characterization of the structure,activity relationships of this series identified key requirements for activity. These include the direction of the sulfonamide bond and substitution patterns on the central phenyl ring. The alkyl spacer between the aromatic head group and the sulfonamide functionality also influenced the HDAC inhibitory activity. One of these compounds, m11.1, also designated PXD101, has entered clinical trials for solid tumors and haematological malignancies. [source]

Rapamycin delays tumor development in murine livers by inhibiting proliferation of hepatocytes with DNA damage,

HEPATOLOGY, Issue 2 2009
Laura Elisa Buitrago-Molina
In this study, everolimus (RAD001) was used to determine the role of mammalian target of rapamycin (mTOR) in hepatocarcinogenesis. We show that RAD001 effectively inhibits proliferation of hepatocytes during chronic liver injury. Remarkably, the ability of RAD001 to impair cell cycle progression requires activation of the DNA damage response; loss of p53 significantly attenuates the antiproliferative effects of mTOR inhibition. RAD001 modulates the expression of specific cell cycle,related proteins and the assembly of cyclin,cyclin-dependent kinase complexes to prevent cell cycle progression. Furthermore, RAD001 sustains the apoptosis sensitivity of hepatocytes during chronic liver injury by inhibiting p53-induced p21 expression. Long-term treatment with RAD001 markedly delays DNA damage,induced liver tumor development. Conclusion: We provide evidence that mTOR inhibition has a substantial effect on sequential carcinogenesis and may offer an effective strategy to delay liver tumor development in patients at risk. (HEPATOLOGY 2009;50:500,509.) [source]

The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38

INTERNATIONAL JOURNAL OF CANCER, Issue 12 2009
Melissa J. LaBonte
Abstract Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. Lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08,11.7 ,M; SN-38 range 3.6,256 nM). Lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas. © 2009 UICC [source]

Protein kinase B modulates the sensitivity of human neuroblastoma cells to insulin-like growth factor receptor inhibition

INTERNATIONAL JOURNAL OF CANCER, Issue 11 2006
Ana S. Guerreiro
Abstract The potential of the novel insulin-like growth factor receptor (IGF-IR) inhibitor NVP-AEW541 as an antiproliferative agent in human neuroblastoma was investigated. Proliferation of a panel of neuroblastoma cell lines was inhibited by NVP-AEW541 with IC50 values ranging from 0.15 to 5 ,M. Experiments using an IGF-IR neutralizing antibody confirmed that the IGF-IR was essential to support growth of neuroblastoma cell lines. The expression levels of the IGF-IR in individual neuroblastoma cell lines did not correlate with the sensitivities to NVP-AEW541, while coexpression of the IGF-IR and the insulin receptor (IR) correlated with lower sensitivity to the inhibitor in some cell lines. Intriguingly, high levels of activation of Akt/protein kinase B (PKB) and phosphorylation of the ribosomal S6 protein were observed in neuroblastoma cell lines with decreased sensitivities to NVP-AEW541. Inhibition of Akt/PKB activity restored the sensitivity of neuroblastoma cells to the IGF-IR inhibitor. Transfection of neuroblastoma cells with activated Akt or ribosomal protein S6 kinase (S6K) decreased the sensitivity of the cells to NVP-AEW541. IGF-I-stimulated proliferation of neuroblastoma cell lines was completely blocked by NVP-AEW541, or by a combination of an inhibitor of phosphoinositide 3-kinase and rapamycin. In addition to its antiproliferative effects, NVP-AEW541 sensitized neuroblastoma cells to cisplatin-induced apoptosis. Together, our data demonstrate that NVP-AEW541 in combination with Akt/PKB inhibitors or chemotherapeutic agents may represent a novel approach to target human neuroblastoma cell proliferation. © 2006 Wiley-Liss, Inc. [source]

Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia

INTERNATIONAL JOURNAL OF CANCER, Issue 12 2006
Hagar Sharabani
Abstract 1,,25-dihydroxyvitamin D3 (1,25D3) is a powerful differentiation agent, which has potential for treatment of myeloid leukemias and other types of cancer, but the calcemia produced by pharmacologically active doses precludes the use of this agent in the clinic. We have shown that carnosic acid, the major rosemary polyphenol, enhances the differentiating and antiproliferative effects of low concentrations of 1,25D3 in human myeloid leukemia cell lines (HL60, U937). Here we translated these findings to in vivo conditions using a syngeneic mouse leukemia tumor model. To this end, we first demonstrated that as in HL60 cells, differentiation of WEHI-3B D, murine myelomonocytic leukemia cells induced by 1 nM 1,25D3 or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 ,M) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G0+G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p. injections of 2 ,g Ro25-4020 in Balb/c mice bearing WEHI-3B D, tumors produced a significant delay in tumor appearance and reduction in tumor size, without significant toxicity. Another analog, 1,25-dihydroxy-16,23Z-diene-20-epi-26,27-hexafluoro-19-nor-cholecalciferol (Ro26-3884) administered at the same dose was less effective than Ro25-4020 and profoundly toxic. Importantly, combined treatment with 1% dry rosemary extract (mixed with food) and 1 ,g Ro25-4020 resulted in a strong cooperative antitumor effect, without inducing hypercalcemia. These results indicate for the first time that a plant polyphenolic preparation and a vitamin D derivative can cooperate not only in inducing leukemia cell differentiation in vitro, but also in the antileukemic activity in vivo. These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia. © 2006 Wiley-Liss, Inc. [source]

Targeting the epidermal growth factor receptor by erlotinib (TarcevaÔ) for the treatment of esophageal cancer

INTERNATIONAL JOURNAL OF CANCER, Issue 7 2006
Andreas P. Sutter
Abstract Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Because of very poor 5-year survival new therapeutic approaches are mandatory. Erlotinib (TarcevaÔ), an inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK), potently suppresses the growth of various tumors but its effect on esophageal carcinoma, known to express EGFR, remains unexplored. We therefore studied the antineoplastic potency of erlotinib in human esophageal cancer cells. Erlotinib induced growth inhibition of the human esophageal squamous cell carcinoma (ESCC) cell lines Kyse-30, Kyse-70 and Kyse-140, and the esophageal adenocarcinoma cell line OE-33, as well as of primary cell cultures of human esophageal cancers. Combining erlotinib with the EGFR-receptor antibody cetuximab, the insulin-like growth factor receptor tyrosine kinase inhibitor tyrphostin AG1024, or the 3-hydroxy-3-methylglutaryl coenzyme. A reductase (HMG-CoAR) inhibitor fluvastatin resulted in additive or even synergistic antiproliferative effects. Erlotinib induced cell cycle arrest at the G1/S checkpoint. The erlotinib-mediated signaling involved the inactivation of EGFR-TK and ERK1/2, the upregulation of the cyclin-dependent kinase inhibitors p21Waf1/CIP1 and p27Kip1, and the downregulation of the cell cycle promoter cyclin D1. However, erlotinib did not induce immediate cytotoxicity or apoptosis in esophageal cancer cells. The inhibition of EGFR-TK by erlotinib appears to be a promising novel approach for innovative treatment strategies of esophageal cancer, as it powerfully induced growth inhibition and cell cycle arrest in human esophageal cancer cells and enhanced the antineoplastic effects of other targeted agents. © 2005 Wiley-Liss, Inc. [source]

The tale of transforming growth factor-beta (TGF,) signaling: A soigné enigma

IUBMB LIFE, Issue 10 2009
Arindam Chaudhury
Abstract Transforming growth factor-beta (TGF,) is a secreted cytokine, which intricately controls a plethora of physiological and pathological processes during development and carcinogenesis. TGF, exerts antiproliferative effects and functions as a tumor suppressor during early stages of tumorigenesis, whereas at later stages it functions as a tumor promoter aiding in metastatic progression through an autocrine TGF, loop. Intricate knowledge of TGF, signaling and its regulation are still evolving. In this review, we make an attempt to showcase the associated enigma of TGF, signaling in its dual functional role as tumor suppressor and metastatic promoter during early and late stages of carcinogenesis, respectively. © 2009 IUBMB IUBMB Life, 61(10): 929,939, 2009 [source]

Butterfat fatty acids differentially regulate growth and differentiation in Jurkat T-cells

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2005
Paolo Bergamo
Abstract Synthetic Conjugated Linoleic Acid mixture (CLA; c9,t11; t10,c12-18:2) has been previously shown to inhibit growth, and enhance apoptosis and IL-2 mRNA synthesis in human lymphoblastic Jurkat T-cells. In this study, two different butterfat types were evaluated and compared for their effects on Jurkat cell viability, oxidative stress, pro-apoptotic activity, and cytokine synthesis: the conventionally produced butterfat (CBF), and organic butterfat (OBF) containing significantly higher amounts of c9,t11 (Rumenic Acid, RA), trans-vaccenic acid (VA; t11-18:1), ,-linolenic acid (ALA), and lower levels of linoleic acid (LA). Results from cell treatment with both butterfat mixtures showed comparable oxidative stress (superoxide production, intracellular GSH depletion,and lipid peroxides yield), NADPH oxidase activation, cytotoxicity (LDH release), and IL-2 transcript level, whereas the effects of enhanced growth-inhibitory and pro-apoptotic activities were associated with OBF treatment. To then investigate each butterfat-induced effect caused by RA, VA, LA, and ALA, cells were exposed to synthetic FA concentrations similar to those from the different butterfats. Higher oxidative stress (superoxide production, intracellular GSH depletion) was induced by ,-linolenic (ALA) and linoleic (LA) incubation (P,<,0.01) and superoxide production was suppressed by specific PKC, inhibitor (Gö 6976) and linked to increased toxicity and IL-2 synthesis inhibition. By contrast, cell treatment with RA increased apoptosis and IL-2 synthesis. These results suggest that a supply of ALA and LA is responsible for BF-induced oxidative stress via PKC,-NADPH oxidase pathway, and that enhanced antiproliferative effects in OBF treated cells is essentially determined by RA-induced pro-apoptotic activity. © 2005 Wiley-Liss, Inc. [source]

Bis-8-hydroxyquinoline and bis-8-hydroxyquinaldine N -substituted amines: A single methyl group structural difference between the two heterocycles, which modulates the antiproliferative effects

JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2010
Sébastien Madonna
The synthesis of a series of bis-8-hydroxyquinoline- and bis-8-hydroxyquinaldine-substituted N -benzyl or thiophenyl amines and their corresponding bis-8-hydroxyquinoline is reported. In vitro growth inhibitory effects of both series have been evaluated. It has been observed that analogs from the bis-8-hydroxyquinoline series exert nanomolar range activity, whereas the antiproliferative activity of the corresponding analogs from the bis-8-hydroxyquinaldine series was found to be drastically lower. Molecular docking and chemical,physical properties account for these observed growth inhibitory differences between the two series of analogs, which differ only by the presence of a methyl group at the 2 position of the heterocyclic ring. J. Heterocyclic Chem., (2010). [source]

In-vitro antiproliferative effects on human tumour cell lines of extracts and jacaranone from Senecio leucanthemifolius Poiret

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2005
M. R. Loizzo
We have studied the cytotoxic activity of extracts and jacaranone from Senecio leucanthemifolius Poiret. Extracts from S. leucanthemifolius were able to inhibit the in-vitro proliferation of a series of human tumour cell lines. The dichloromethane extract demonstrated effective cytotoxic activity with an IC50 of 20.1 ,g mL,1 on the large cell carcinoma cell line COR-L23. The ethyl acetate extract showed an IC50 value of 5.0 ,g mL,1 and the butanol extract an IC50 value of 6.4 ,g mL,1 on the same cell line. A major active constituent of the dichloromethane extract was shown to be jacaranone, which was demonstrated to have a very strong activity against all of the tumour cell lines with IC50 values between 2.86 and 3.85 ,g mL,1, although it did not account for all the activity observed. Constituents of S. leucanthemifolius extracts were identified by GC/MS analysis and NMR. [source]

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit vascular smooth muscle cell proliferation via differential effects on the cell cycle

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2003
Gavin Brooks
ABSTRACT Abnormal vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of both atherosclerosis and restenosis. Recent studies suggest that high-dose salicylates, in addition to inhibiting cyclooxygenase activity, exert an antiproliferative effect on VSMC growth both in-vitro and in-vivo. However, whether all non-steroidal anti-inflammatory drugs (NSAIDs) exert similar antiproliferative effects on VSMCs, and do so via a common mechanism of action, remains to be shown. In this study, we demonstrate that the NSAIDs aspirin, sodium salicylate, diclofenac, ibuprofen, indometacin and sulindac induce a dose-dependent inhibition of proliferation in rat A10 VSMCs in the absence of significant cytotoxicity. Flow cytometric analyses showed that exposure of A10 cells to diclofenac, indometacin, ibuprofen and sulindac, in the presence of the mitotic inhibitor, nocodazole, led to a significant G0/G1 arrest. In contrast, the salicylates failed to induce a significant G1 arrest since flow cytometry profiles were not significantly different from control cells. Cyclin A levels were elevated, and hyperphosphorylated p107 was present at significant levels, in salicylate-treated A10 cells, consistent with a post-G1/S block, whereas cyclin A levels were low, and hypophosphorylated p107 was the dominant form, in cells treated with other NSAIDs consistent with a G1 arrest. The ubiquitously expressed cyclin-dependent kinase (CDK) inhibitors, p21 and p27, were increased in all NSAID-treated cells. Our results suggest that diclofenac, indometacin, ibuprofen and sulindac inhibit VSMC proliferation by arresting the cell cycle in the G1 phase, whereas the growth inhibitory effect of salicylates probably affects the late S and/or G2/M phases. Irrespective of mechanism, our results suggest that NSAIDs might be of benefit in the treatment of certain vasculoproliferative disorders. [source]

Alsterpaullone, a novel cyclin-dependent kinase inhibitor, induces apoptosis by activation of caspase-9 due to perturbation in mitochondrial membrane potential,

MOLECULAR CARCINOGENESIS, Issue 4 2003
Tyler Lahusen
Abstract The majority of human neoplasms have aberrations in the retinoblastoma pathway due to hyperactivation of cyclin-dependent kinases (CDK). Based on this observation, novel small molecules, such as flavopiridol and UCN-01, are being developed and are currently being tested in the clinic. Efforts to develop CDK modulators led us to the discovery of a novel class of CDK inhibitors, the paullones [Cancer Res 1999;59:2566]. Initial studies demonstrated that paullones inhibit CDKs in vitro, thereby blocking cell-cycle progression. However, the exact mechanism for the antiproliferative effects of paullones was never explored. In this report, we demonstrate for the first time that the most potent paullone, alsterpaullone (Alp), induced apoptosis and promoted loss in clonogenicity in the Jurkat cell line. Alp caused early activation of both caspase-8 and -9, leading to cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, apoptosis by Alp was not associated with loss in anti-apoptotic proteins such as XIAP or BCL-XL. Pre-incubation with cell-permeable inhibitors z-Asp(OMe)-Glu(OMe)-Val-Asp(Ome)-fluoromethylketone and benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (ZVAD) blocked Alp-induced apoptosis. Moreover, the general caspase inhibitor ZVAD blocked the cleavage and activation of most caspases tested except caspase-9. Studies of mitochondrial membrane potential also demonstrated that Alp is able to disrupt mitochondrial potential in the presence of ZVAD, suggesting that the activation of caspase-9 by Alp follows mitochondrial perturbation. Pre-incubation of Jurkat cells with ZVAD did not prevent the depletion of cyclin D3, loss of CDK, or cell-cycle arrest by Alp. In summary, these experiments suggest that Alp activates caspase-9 via mitochondrial perturbation. Active caspase-9 cleaves and activates caspase-8 and caspase-3, leading to apoptosis. In the presence of the general caspase inhibitor ZVAD, the cell-cycle effects of Alp are unaltered while apoptosis is blocked, suggesting that the CDK effects of Alp are not sufficient for Alp-induced apoptosis. Additional studies with paullones are warranted to further characterize their preclinical effects and to explore their potential use in the clinical setting. Published 2003 Wiley-Liss, Inc. [source]

Bioactive aldehydes from diatoms block the fertilization current in ascidian oocytes

MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 1 2003
Elisabetta Tosti
Abstract The effects of bioactive aldehydes from diatoms, unicellular algae at the base of the marine food web, were studied on fertilization and early development processes of the ascidian Ciona intestinalis. Using whole-cell voltage clamp techniques, we show that 2- trans -4- trans -decadienal (DD) and 2- trans -4- cis -7- cis -decatrienal (DT) inhibited the fertilization current which is generated in oocytes upon interaction with the spermatozoon. This inhibition was dose-dependent and was accompanied by inhibition of the voltage-gated calcium current activity of the plasma membrane. DD and DT did not inhibit the subsequent contraction of the cortex. Moreover, DD specifically acted as a fertilization channel inhibitor since it did not affect the steady state conductance of the plasma membrane or gap junctional (GJ) communication within blastomeres of the embryo. On the other hand, DD did affect actin reorganization even though the mechanism of action on actin filaments differed from that of other actin blockers. Possibly this effect on actin reorganization was responsible for the subsequent teratogenic action on larval development. The effect of DD was reversible if oocytes were washed soon after fertilization indicating that DD may specifically target certain fertilization mechanisms. Thus, diatom reactive aldehydes such as DD may have a dual effect on reproductive processes, influencing primary fertilization events such as gating of fertilization channels and secondary processes such as actin reorganization which is responsible for the segregation of cell lineages. These findings add to a growing body of evidence on the antiproliferative effects of diatom-derived aldehydes. Our results also report, for the first time, on the action of a fertilization channel blocker in marine invertebrates. Mol. Reprod. Dev. 66: 72,80, 2003. © 2003 Wiley-Liss, Inc. [source]

Mistletoe lectin-I augments antiproliferative effects of the PPAR, agonist rosiglitazone on human malignant melanoma cells

PHYTOTHERAPY RESEARCH, Issue 9 2010
Christian Freudlsperger
Abstract As malignant melanoma cells are highly resistant to conventional chemotherapy, survival rates after tumor spread remain poor and hence there is an urgent need for new therapeutic options. For both mistletoe lectin-I (ML-I) and the thiazolidinediones as synthetic ligands of the peroxisome proliferator-activated receptor , (PPAR,) an antiproliferative effect on malignant melanoma cells has previously been shown. Hence, the aim of this study was to investigate whether the combination of ML-I and the PPAR, ligand rosiglitazone is more efficacious in the treatment of malignant melanoma cells than either agent alone. Proliferation of three human melanoma cell lines treated with ML-I, rosiglitazone and the combination of both was measured in a broad concentration range (0.0001,100,,g/mL) using the XTT cell proliferation assay. Combined application tremendously increased the antiproliferative effect on all three melanoma cell lines compared with single agent treatment. In comparison with the single use of rosiglitazone, the combination with ML-I significantly increased the inhibition of cell growth by 51,79% and in comparison with the single use of ML-I by 9,32%, respectively. In conclusion, this study shows that the combination of ML-I with rosiglitazone significantly augments their antiproliferative effect on malignant melanoma cells in comparison with their single agent application, which might be a promising tool for further therapeutic studies. Copyright © 2010 John Wiley & Sons, Ltd. [source]

Ganoderma lucidum extract attenuates the proliferation of hepatic stellate cells by blocking the PDGF receptor

PHYTOTHERAPY RESEARCH, Issue 6 2009
Guei-Jane Wang
Abstract Hepatic fibrosis is an outcome of chronic liver diseases. The activation and proliferation of hepatic stellate cells (HSCs) is a key event in liver injury. The fruiting body of Ganoderma lucidum has long been a popular oriental medicine for treating liver diseases. The aim of this present study was to investigate the antiproliferative effects of the triterpenoid-rich extract (GLT) of G. lucidum in a cell line of rat HSCs (HSC-T6) stimulated with platelet-derived growth factor (PDGF)-BB. DNA synthesis was investigated by bromodeoxyuridine (BrdU) incorporation. Flow cytometry using propidium iodide (PI) labeling was carried out to analyse the cell cycle distribution and apoptosis. , -Smooth muscle actin (, -SMA) was used to evaluate extracellular matrix deposition, and western blotting was performed to measure cyclins D1 and D2, and phosphorylation of the PDGF, -receptor (PDGF,R), Akt and JNK. The results indicated that the GLT attenuated BrdU incorporation in a concentration-dependent manner with an IC50 of 8.52 ± 0.33 µg/mL. The inhibitory effect of the GLT was associated with downregulation of cyclins D1 and D2, and PDGF,R and Akt phosphorylation, upregulation of JNK phosphorylation, and a reduction in , -SMA expression. These results indicated that G. lucidum inhibits PDGF-BB-activated HSC proliferation possibly through blocking PDGF,R phosphorylation, thereby indicating its efficacy for preventing and treating hepatic fibrosis. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Antiproliferative effect of flavonoids and sesquiterpenoids from Achillea millefolium s.l. on cultured human tumour cell lines

PHYTOTHERAPY RESEARCH, Issue 5 2009
Boglárka Csupor-Löffler
Abstract The antiproliferative activities of n -hexane, chloroform, aqueous-methanol and aqueous extracts of the aerial parts of the Achillea millefolium aggregate on three human tumour cell lines were investigated by means of MTT assays. The chloroform-soluble extract exerted high tumour cell proliferation inhibitory activities on HeLa and MCF-7 cells, and a moderate effect on A431 cells; accordingly, it was subjected to detailed bioactivity-guided fractionation. As a result of the multistep chromatographic purifications (VLC, CPC, PLC, gel filtration), five flavonoids (apigenin, luteolin, centaureidin, casticin and artemetin) and five sesquiterpenoids (paulitin, isopaulitin, psilostachyin C, desacetylmatricarin and sintenin) were isolated and identified by spectroscopic methods. The antiproliferative assay demonstrated that centaureidin is the most effective constituent of the aerial parts of yarrow: high cell growth inhibitory activities were observed especially on HeLa (IC50 0.0819 µm) and MCF-7 (IC50 0.1250 µm) cells. Casticin and paulitin were also highly effective against all three tumour cell lines (IC50 1.286,4.76 µm), while apigenin, luteolin and isopaulitin proved to be moderately active (IC50 6.95,32.88 µm). Artemetin, psilostachyin C, desacetylmatricarin and sintenin did not display antiproliferative effects against these cell lines. This is the first report on the occurrence of seco -pseudoguaianolides (paulitin, isopaulitin and psilostachyin C) in the Achillea genus. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Antiproliferative effects of different plant parts of Panax notoginseng on SW480 human colorectal cancer cells

Antimutagenic and antiproliferative effects of roasted and defatted peanut dregs on human leukemic U937 and HL-60 cells

The folate metabolic enzyme ALDH1L1 is restricted to the midline of the early CNS, suggesting a role in human neural tube defects

THE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 2 2007
Todd E. Anthony
Abstract Folate supplementation prevents up to 70% of human neural tube defects (NTDs), although the precise cellular and metabolic sites of action remain undefined. One possibility is that folate modulates the function of metabolic enzymes expressed in cellular populations involved in neural tube closure. Here we show that the folate metabolic enzyme ALDH1L1 is cell-specifically expressed in PAX3-negative radial glia at the midline of the neural tube during early murine embryogenesis. Midline restriction is not a general property of this branch of folate metabolism, as MTHFD1 displays broad and apparently ubiquitous expression throughout the neural tube. Consistent with previous work showing antiproliferative effects in vitro, ALDH1L1 upregulation during central nervous system (CNS) development correlates with reduced proliferation and most midline ALDH1L1+ cells are quiescent. These data provide the first evidence for localized differences in folate metabolism within the early neural tube and suggest that folate might modulate proliferation via effects on midline Aldh1l1+ cells. To begin addressing its role in neurulation, we analyzed a microdeletion mouse strain lacking Aldh1l1 and observed neither increased failure of neural tube closure nor detectable proliferation defects. Although these results indicate that loss-of-function Aldh1l1 mutations do not impair these processes in mice, the specific midline expression of ALDH1L1 and its ability to dominantly suppress proliferation in a folate responsive manner may suggest that mutations contributing to disease are gain-of-function, rather than loss-of-function. Moreover, a role for loss-of-function mutations in human NTDs remains possible, as Mthfr null mice do not develop NTDs even though MTHFR mutations increase human NTD risk. J. Comp. Neurol. 500:368,383, 2007. © 2006 Wiley-Liss, Inc. [source]

Activation of AMP-activated protein kinase by adiponectin rescues salivary gland epithelial cells from spontaneous and interferon-,,induced apoptosis

ARTHRITIS & RHEUMATISM, Issue 2 2010
Stergios Katsiougiannis
Objective Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltrates associated with destruction of salivary gland epithelial cells (SGECs) induced mainly by apoptosis. Adiponectin is an immunoregulatory hormone. We have previously shown that SGECs from patients with primary SS as well as from controls differentially express adiponectin. SGECs derived from patients with primary SS constitutively produce and secrete adiponectin in higher quantities. The aim of this study was to investigate the effect of adiponectin on the proliferation and apoptosis of SGECs. Methods Cultured, non-neoplastic SGECs were treated with recombinant human adiponectin, and the rate of cell proliferation was assessed. Spontaneous and interferon-, (IFN,),induced apoptosis was evaluated with a specific single-stranded DNA enzyme-linked immunosorbent assay. The AMP-activated protein kinase (AMPK) inhibitor Compound C was used to test the involvement of AMPK in adiponectin effects. Western blotting was applied to detect the phosphorylation levels of AMPK after adiponectin treatment. Results Adiponectin treatment resulted in a dose-dependent suppression of proliferation of SGECs from patients with primary SS and control donors. Adiponectin protected cells from spontaneous as well as from IFN,-induced apoptosis. Furthermore, the antiapoptotic effects of adiponectin were dependent upon AMPK phosphorylation at Thr172, since pretreatment of SGECs with Compound C abolished the adiponectin protective effect. Conclusion Adiponectin exerted antiproliferative effects on SGECs without inducing apoptosis and protected SGECs from spontaneous as well as from IFN,-induced apoptosis through an AMPK-dependent pathway. Our observations suggest that adiponectin may protect SGECs in this specific inflammatory milieu, providing a potential pathway through which AMPK may regulate cell survival under energy stress conditions such as autoimmune inflammation. [source]

Folate receptor , as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients

ARTHRITIS & RHEUMATISM, Issue 1 2009
Joost W. Van Der Heijden
Objective To determine the expression of folate receptor , (FR,) in synovial biopsy tissues and peripheral blood lymphocytes from rheumatoid arthritis (RA) patients and to identify novel folate antagonists that are more selective in the targeting and internalization of FR, than methotrexate (MTX). Methods Immunohistochemistry and computer-assisted digital imaging analyses were used for the detection of FR, protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FR, messenger RNA (mRNA) levels were determined by reverse transcription,polymerase chain reaction analysis. Binding affinities of FR, for folate antagonists were assessed by competition experiments for 3H-folic acid binding on FR,-transfected cells. Efficacy of FR,-mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FR,-transfected cells. Results Immunohistochemical staining of RA synovial tissue showed high expression of FR, on macrophages in the intimal lining layer and synovial sublining, whereas no staining was observed in T cell areas or in control synovial tissue. Consistently, FR, mRNA levels were highest in synovial tissue extracts and RA monocyte-derived macrophages, but low in peripheral blood T cells and monocytes. Screening of 10 new-generation folate antagonists revealed 4 compounds for which FR, had a high binding affinity (20,77-fold higher than for MTX). One of these, the thymidylate synthase inhibitor BCG 945, displayed selective targeting against FR,-transfected cells. Conclusion Abundant FR, expression on activated macrophages in synovial tissue from RA patients deserves further exploration for selective therapeutic interventions with high-affinity,binding folate antagonists, of which BCG 945 may be a prototypical representative. [source]

Heparin-binding epidermal growth factor-like growth factor isoforms and epidermal growth factor receptor/ErbB1 expression in bladder cancer and their relation to clinical outcome

CANCER, Issue 10 2007
Christopher Kramer MD
Abstract BACKGROUND. Cleavage of membrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields a soluble HB-EGF isoform (sHB-EGF), which is an activating epidermal growth factor receptor (EGFR) ligand and a C-terminal fragment HB-EGF-C acting directly in the nucleus. In bladder cancer, overexpression of both HB-EGF and EGFR have been observed, but to the authors' knowledge the prognostic significance of different modes of HB-EGF signaling have remained unclear. METHODS. Expression and intracellular localization of HB-EGF and EGFR were examined by immunohistochemistry in paraffin-embedded specimens from 121 patients who underwent cystectomy for bladder cancer. Tumor stage was pTis/pT1 in 7 patients, pT2 in 41 patients, pT3 in 55 patients, and pT4 in 18 patients. Lymph node metastases were present in 32 patients. RESULTS. Using an antibody directed against the C-terminal domain, HB-EGF expression was detected in the cytoplasm or in the nucleus of tumor cells. EGFR staining was uniform at the plasma membrane. The actuarial 5-year cancer-specific survival of patients with tumors with predominant nuclear HB-EGF staining was 28% compared with 57% if HB-EGF staining was predominantly cytoplasmic (P = .027). Disease outcome of patients with a ,mixed' HB-EGF staining pattern was found to be between that of the 2 former groups. In agreement with previous studies, strong EGFR expression was associated with poor prognosis. Despite strong EGFR expression, predominant cytoplasmic HB-EGF staining was associated with a more favorable outcome, whereas a predominant nuclear pattern defined a subgroup with extremely poor prognosis (5-year tumor-specific survival of 55% vs 13%, respectively; P = .026). CONCLUSIONS. The current study results confirm that EGFR expression is significantly correlated with disease-specific mortality but that the outcome is also influenced by the mode of HB-EGF signaling. Additional nuclear HB-EGF signaling, indicative of increased cleavage of proHB-EGF, appears to enhance the adverse activities. Cytoplasmic HB-EGF staining likely reflects proHB-EGF, which may also exert antiproliferative effects. Cancer 2007. © 2007 American Cancer Society. [source]