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Growth Inhibitory Effects (growth + inhibitory_effects)
Selected AbstractsGrowth inhibitory effects of pegylated IFN ,-2b on human liver cancer cells in vitro and in vivoLIVER INTERNATIONAL, Issue 8 2006Hirohisa Yano Abstract: Purpose: We investigated the effects of pegylated IFN-,2b (PEG-IFN-,2b) on the growth of human liver cancer cells. Methods: The effect of PEG-IFN-,2b on the proliferation of 13 liver cancer cell lines was investigated in vitro. Chronological changes in growth and IFN-, receptor-2 (IFNAR-2) expression were monitored in hepatocellular carcinoma (HCC) cells (HAK-1B) cultured with PEG-IFN-,2b. After HAK-1B cells were transplanted into nude mice, various doses of PEG-IFN-,2b or IFN-,2b were administered, and tumor volume, weight, histology, and IFNAR-2 expression were examined. Results: PEG-IFN-,2b inhibited the growth of nine cell lines with apoptosis in a dose- and time-dependent manner. Continuous contact with PEG-IFN-,2b induced time-dependent growth inhibition and down-regulation of IFNAR-2 expression. PEG-IFN-,2b induced a dose-dependent decrease in tumor volume and weight, a significant increase of apoptotic cells, and a decrease in IFNAR-2 expression in the tumor. The clinical dose for chronic hepatitis C was also effective. The antitumor effect of PEG-IFN-,2b was significantly stronger than that of non-PEG-IFN-,2b in vivo. Conclusions: Continuous contact with PEG-IFN-,2b induces strong antitumor effects and the down-regulation of IFNAR-2 in HCC cells. The data suggest potential clinical application of PEG-IFN-,2b for the prevention and treatment of HCC. [source] BSc2118 is a novel proteasome inhibitor with activity against multiple myelomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2010Jan Sterz Abstract Objectives:, The ubiquitin,proteasome system emerged as a new therapeutic target in cancer treatment. The purpose of this study was to elucidate the effects of the novel proteasome inhibitor BSc2118 on t(4;14) positive and negative multiple myeloma (MM) cells and normal peripheral blood mononuclear cells (PBMNC). Methods:, Human MM cell lines OPM-2, RPMI-8226, and U266 and primary MM cells from bone marrow aspirates were exposed to BSc2118. Cytotoxicity levels were evaluated using the MTT-test. BSc2118-induced apoptosis was analyzed by annexin-V assay. Further methods used included proteasomal activity determination, cell cycle analysis, western blot, and transcription factor assays. Results:, In OPM-2, RPMI-8226, U266 cell lines and primary MM cells, BSc2118 caused dose-dependent growth inhibitory effects. After 48 h, dose-dependent apoptosis occurred both in cell lines and primary myeloma cells irrespective of t(4;14). A significant G2-M cell cycle arrest occurred after 24 h. Furthermore, we observed a marked inhibition of intracellular proteasome activity, an increase in intracellular p21 levels, and an inhibition of NF-,B activation. The toxicity against PBMNC remained low, suggesting a broad therapeutic range of this agent. Conclusion:, Taken together, BSc2118 shows significant antimyeloma activity and may be considered as a promising agent in cancer drug development. [source] Vorinostat increases carboplatin and paclitaxel activity in non-small cell lung cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2010Taofeek K. Owonikoko Abstract We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 hr of continuous drug exposure. Vorinostat (1 ,M) inhibited growth by: 17% ± 7% in A549, 28% ± 6% in 128-88T, 39% ± 8% in Calu1 and 41% ± 7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel led to significantly greater growth inhibition than chemotherapy alone in all 4 cell lines. Vorinostat (1 ,M) synergistically increased the growth inhibitory effects of carboplatin/paclitaxel in 128-88T cells. When colony formation was measured after drug withdrawal, vorinostat significantly increased the effects of carboplatin but not paclitaxel. The % colony formation was control 100%; 1 ,M vorinostat, 83% ± 10%; 5 ,M carboplatin, 41% ± 11%; carboplatin/vorinostat, 8% ± 4%; 2 nM paclitaxel, 53% ± 11%; paclitaxel/vorinostat, 46% ± 21%. In A549 and 128-88T, vorinostat potentiated carboplatin induction of gamma-H2AX (a DNA damage marker) and increased ,-tubulin acetylation (a marker for stabilized mictrotubules). In A549, combination of vorinostat with paclitaxel resulted in a synergistic increase in ,-tubulin acetylation, which reversed upon drug washout. We conclude that vorinostat interacts favorably with carboplatin and paclitaxel in NSCLC cells, which may explain the provocative response observed in our clinical trial. This likely involves a vorinostat-mediated irreversible increase in DNA damage in the case of carboplatin and a reversible increase in microtubule stability in the case of paclitaxel. [source] The use of histone deacetylase inhibitor FK228 and DNA hypomethylation agent 5-azacytidine in human bladder cancer therapyINTERNATIONAL JOURNAL OF CANCER, Issue 8 2007Jose A. Karam Abstract The long-term disease-free survival in patients with metastatic transitional cell carcinoma (TCC) is still considerably low. Novel chemotherapeutic agents are needed to decrease the morbidity and mortality of TCC. In this study, we have evaluated several epigenetic modifiers for their therapeutic application in bladder cancer. Both histone deacetylase inhibitors (FK228, TSA) and DNA hypomethylating agent (5-Azacytidine) were tested using in vitro assays such as cell viability, cell cycle analysis and western blot to determine their mechanisms of action. Drug combination experiments were also designed to study any additive or synergistic effects of these agents. In addition, two bladder cancer xenograft models (one subcutaneous and one orthotopic) were employed to assess the therapeutic efficacy of these agents in vivo. Three agents exhibited various growth inhibitory effects on 5 different TCC cell lines in a dose- and time-dependent manner. In addition to G2/M cell cycle arrest, FK228 is more potent in inducting apoptosis than the two other single agents, and combination of both FK228 and 5-Aza further enhances this effect. p21 induction is closely associated with FK228 or TSA but not 5-Aza, which is mediated via p53-independent pathway. Consistent with in vitro results, FK228 exhibited a significant in vivo growth inhibition of TCC tumor in both subcutaneous and orthotopic xenograft models. FK228 is a potent chemotherapeutic agent for TCC in vivo with minimal undesirable side effects. The elevated p21 level mediated via p53 independent pathway is a hallmark of FK228 mechanism of action. © 2007 Wiley-Liss, Inc. [source] Differential response to phytoestrogens in endocrine sensitive and resistant breast cancer cells in vitroINTERNATIONAL JOURNAL OF CANCER, Issue 3 2006Jane L. Limer Abstract Women approaching menopause increasingly investigate alternatives to hormone replacement therapy. Plant phytoestrogens are being promoted as "natural" alternatives but there is a lack of substantive data to advocate their safe use in breast cancer patients receiving tamoxifen (TAM), or in those who have relapsed. The aim of our study was to investigate the proliferative effects and mode of action of the phytoestrogens genistein, daidzein and coumestrol on TAM-sensitive (-s) and resistant (-r) breast cancer cells under in vitro conditions designed to mimic the hormonal environment of the pre- and post-menopausal breast. At physiological concentrations (<10 ,M) and under reduced estrogen (E2) conditions, genistein was mitogenic to TAM-s cells with TAM-r cells generally refractory. Daidzein and coumestrol were growth stimulatory irrespective of TAM sensitivity. Transcriptional activity was ERE-mediated. Combining phytoestrogens with E2 (simulating the pre-menopausal breast environment) had no effect on growth of TAM-s or TAM-r cells. Addition of 4-HT mimicked the hormonal environment in post-menopausal breast cancer patients receiving TAM. The growth inhibitory effects of 4-HT were abrogated in TAM-s cells when combined with genistein and coumestrol, and to a lesser extent, daidzein, where significant growth stimulatory effects were observed. In TAM-r cells, proliferation did not exceed control values. At phytoestrogen concentrations above 10 ,M, growth inhibitory effects were seen, irrespective of estrogenic environment or cell sensitivity to TAM. Our in vitro data suggests that phytoestrogens could have potentially adverse mitogenic effects on tumour cells and should probably be avoided by patients who remain sensitive to TAM or in those with pre-existing and possibly undiagnosed breast tumours. © 2006 Wiley-Liss, Inc. [source] Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell linesJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2004William F. Holmes Apoptosis is also known as programmed cell death. Apoptosis plays an essential role in maintaining normal tissue and cell physiology in multicellular organisms. Clearance of aberrant or pre-cancerous cells occurs through the induction of apoptosis. It has been reported that many tumors and tumor cell lines have dysfunctional apoptosis signaling, causing these tumors to escape immune monitoring and internal cellular control mechanisms. One potential cause of this dysfunctional apoptosis is the tumor suppressor p53, an important regulator of growth arrest and apoptosis that is mutated in over 50% of all cancers. Retinoids have great potential in the areas of cancer therapy and chemoprevention. While some tumor cells are sensitive to the growth inhibitory effects of natural retinoids such as all- trans -retinoic acid (ATRA), many ovarian tumor cells are not. 6-[3-(1-Admantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and fenretinide N -[4-hydroxyphenyl] retinamide (4-HPR) are conformationally restricted synthetic retinoids that induce growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. Recently, we have identified the molecular pathways of apoptosis induced by treatment of ovarian carcinoma cells with mutated p53 by CD437 and 4-HPR. © 2004 Wiley-Liss, Inc. [source] JS-K, a novel non-ionic diazeniumdiolate derivative, inhibits Hep 3B hepatoma cell growth and induces c-Jun phosphorylation via multiple MAP kinase pathwaysJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2003Zhenggang Ren JS-K, a non-ionic diazeniumdiolate derivative, is capable of arylating nucleophiles and spontaneously generating nitric oxide (NO) at physiological pH. This recently synthesized low molecular weight compound is shown here to be an inhibitor of cell growth with concomitant activation of mitogen-activated protein kinase (MAPK) members ERK, JNK, and p38 and their downstream effectors c-Jun and AP-1. Inhibitors of these MAPK pathways abrogated the growth inhibitory actions of JS-K. In addition to the well-described actions of JNK as a kinase for c-Jun, we show that c-Jun is also an ERK target. Furthermore, JS-K generated NO in culture and NO inhibitors antagonized both MAPK induction and the growth inhibitory effects of JS-K. These results suggest two possible mechanisms for the mediation of JS-K growth inhibitory actions, namely NO-induction of MAPK pathway constituents as well as possible arylation reactions. The data support the idea that prolonged MAPK activation by JS-K action is important in mediating its growth-inhibitory actions. JS-K thus represents a promising platform for novel growth inhibitory analog synthesis. J. Cell. Physiol. 197: 426,434, 2003© 2003 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 effectsJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2010Sébastien 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] Mesalazine downregulates c-Myc in human colon cancer cells.ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 12 2007A key to its chemopreventive action? Summary Background, Dysplasia and malignant transformation of colonocytes in ulcerative colitis are associated with overexpression of c-Myc and genes regulating cell survival. 5-Aminosalicylates such as mesalazine may reduce the development of colorectal cancer in ulcerative colitis, but the mechanisms of its chemopreventive action are not clear. Aims, To examine whether mesalazine affects the expression of c-Myc in human colon cancer cell lines. Methods, Human colon cancer cells were treated with vehicle or mesalazine (4 mm or 40 mm). We examined: (i) mRNA expression by gene array, (ii) protein expression by Western blotting and immunohistochemistry and (iii) apoptosis by Annexin V labelling. Results, Mesalazine significantly reduced expression of c-Myc mRNA and protein. Conclusions, Mesalazine downregulates gene and protein expression of c-Myc. The apoptotic and growth inhibitory effects of mesalazine are dose-dependent. Expression of c-Myc is significantly reduced by mesalazine 40 mm. [source] Free Zn2+ enhances inhibitory effects of EGCG on the growth of PC-3 cellsMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 4 2008Shi-li Sun Abstract Epigallocatechin-3-gallate (EGCG), a major component of green tea, has both preventive and therapeutic beneficial actions in prostate cancer. In the present study, we compared the growth inhibitory effects and the antioxidant and ability to modify cell membrane permeation of zinc-EGCG complex and Zn2+/EGCG mixture on androgen-insensitive prostate cancer (PC-3) cells. It was noted that free Zn2+ enhanced the growth inhibitory effects of EGCG on PC-3 cells at 160 ,mol/L concentration, whereas zinc-EGCG complex was ineffective. EGCG showed potent free radical scavenging ability in the presence of Zn2+. EGCG in the presence of Zn2+ was more effective than EGCG alone in enhancing the permeability of the cell membrane, whereas zinc-EGCG complex had no effect on PC-3 cell membrane permeability. These results indicate that though Zn2+ enhanced the action of EGCG on PC-3 cells, zinc-EGCG complex is highly unlikely to be formed in the presence of Zn2+ and EGCG to explain the potentiating action of Zn2+ on the growth inhibitory property of EGCG on PC-3 cells. [source] Role of insulin-like growth factor binding proteins in 1,,25-dihydroxyvitamin D3 -induced growth inhibition of human prostate cancer cellsTHE PROSTATE, Issue 1 2005LaMonica V. Stewart Abstract BACKGROUND The mechanisms underlying 1,,25-dihydroxyvitamin D3 (1,25D)-induced growth inhibition of human prostate cancer cells have not been fully elucidated. To determine whether alterations in the insulin-like growth factor (IGF) signaling axis are associated with 1,25D-induced growth inhibition, we examined the ability of 1,25D to regulate expression of IGF binding proteins (IGFBPs) in human prostate cancer cell lines. METHODS Northern and Western blot analyses were used to detect 1,25D-induced alterations in IGFBP expression. Additional in vitro studies were performed to determine the role of IGFBP-3 in 1,25D-induced growth inhibition. RESULTS 1,25D decreased mRNA levels of the growth stimulatory IGFBP-2 and induced IGFBP-3 mRNA in LNCaP and C4-2 cells. 1,25D treatment also increased secreted IGFBP-3 protein levels in prostate cancer cell lines sensitive to 1,25D growth inhibition but had little effect on IGFBP-3 expression in 1,25D-resistant DU145 cells. However, recombinant IGFBP-3 had only a minor effect on LNCaP cell growth in the presence of serum. Furthermore, siRNA duplexes that reduced IGFBP-3 expression did not alter 1,25D growth inhibition in either LNCaP or PC-3 cell lines grown in serum-containing media. CONCLUSIONS Our studies indicate 1,25D-induced up-regulation of IGFBP-3 is not required for the growth inhibitory effects of 1,25D in prostate cancer cells grown in serum-containing media. © 2005 Wiley-Liss, Inc. [source] In vitro and in vivo antineoplastic activity of a novel bromopyrrole and its potential mechanism of actionBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2010Sheng Xiong Background and purpose:, Many bromopyrrole compounds have been reported to have in vitro antineoplastic activity. In a previous study, we isolated N-(4, 5-dibromo-pyrrole-2-carbonyl)-L-amino isovaleric acid methyl ester (B6) from marine sponges. Here, we investigated the in vitro and in vivo antineoplastic activity of B6 and its potential mechanism. Experimental approach:, The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine the in vitro antineoplastic activity of B6. Flow cytometry, western blot analysis and morphological observations were used to investigate its mechanism of action. A mouse xenograft model was used to determine its in vivo activity. Key results:, B6 inhibited the proliferation of various human cancer cells in vitro, with highest activity on LOVO and HeLa cells. B6 also exhibited significant growth inhibitory effects in vivo in a xenograft mouse model. Acute toxicity analysis suggested that B6 has low toxicity. B6-treated cells arrested in the G1 phase of the cell cycle and had an increased fraction of sub-G1 cells. In addition, the population of Annexin V-positive/propidium iodide-negative cells increased, indicating the induction of early apoptosis. Indeed, B6-treated cells exhibited morphologies typical of cells undergoing apoptosis. Western blotting showed cleaved forms of caspase-9 and caspase-3 in cells exposed to B6. Moreover, B6-promoted Ca2+ release and apoptosis was associated with elevated intracellular Ca2+concentration. Conclusions and implications:, B6 has significant antineoplastic activity in vitro as well as in vivo. It inhibits tumour cell proliferation by arresting the cell cycle and inducing apoptosis. With its low toxicity, B6 represents a promising antineoplastic, primary compound. [source] Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2CANCER SCIENCE, Issue 7 2007Makoto Ishikawa Adiponectin, a circulating peptide hormone produced in adipose tissue, has been shown to be reduced in the plasma of patients with cancer, suggesting that this adipokine may be mechanically involved in the pathogenesis of adiposity-related carcinogenesis. In this study, we examined the expression of adiponectin receptors (AdipoR1 and AdipoR2) and assessed the function of adiponectin in gastric cancer. All of the six gastric cancer cell lines significantly expressed mRNA and protein of both receptors with variable levels. Addition of 30 µg/mL adiponectin potently induced apoptosis and inhibited the proliferation of AZ521 and HCG27. Down-regulation of either AdipoR1 or AdipoR2 by specific siRNA significantly suppressed the growth inhibitory effects of adiponectin in both cell lines. Moreover, a local injection of adiponectin markedly inhibited the growth of AZ521 inoculated subcutaneously in nude mice. Similarly, the continuous intraperitoneal infusion of adiponectin effectively suppressed the development of peritoneal metastasis of AZ521. Adiponectin negatively regulates the progression of gastric cancer cells possibly through both AdipoR1 and AdipoR2. Although adiponectin was already reported to have antiangiogenic effects, our results suggest that the antitumor effect of adiponectin was, at least partially, dependent on the direct effects on tumor cells. (Cancer Sci 2007; 98: 1120,1127) [source] Effects of the flavonoid baicalin and its metabolite baicalein on androgen receptor expression, cell cycle progression and apoptosis of prostate cancer cell linesCELL PROLIFERATION, Issue 5 2001S. Chen Recent studies on the Chinese herbal medicine PC SPES showed biological activities against prostate cancer in vitro, in vivo and in patients with advanced stages of the disease. In investigating its mode of action, we have isolated a few of the active compounds. Among them, baicalin was the most abundant (about 6%) in the ethanol extract of PC SPES, as determined by HPLC. Baicalin is known to be converted in vivo to baicalein by the cleavage of the glycoside moiety. Therefore, it is useful to compare their activities in vitro. The effects of baicalin and baicalein were studied in androgen-positive and -negative human prostate cancer lines LNCaP and JCA-1, respectively. Inhibition of cell growth by 50% (ED50) in LNCaP cells was seen at concentrations of 60.8 ± 3.2 and 29.8 ± 2.2 µm baicalin and baicalein, respectively. More potent growth inhibitory effects were observed in androgen-negative JCA-1 cells, for which the ED50 values for baicalin and baicalein were 46.8 ± 0.7 and 17.7 ± 3.4, respectively. Thus, it appears that cell growth inhibition by these flavonoids is independent of androgen receptor status. Both agents (1) caused an apparent accumulation of cells in G1 at the ED50 concentration, (2) induced apoptosis at higher concentrations, and (3) decreased expression of the androgen receptor in LNCaP cells. [source] Synthesis of 9,9-Dialkyl-4,5-diazafluorene Derivatives and Their Structure,Activity Relationships Toward Human Carcinoma Cell LinesCHEMMEDCHEM, Issue 4 2010Qiwei Wang Abstract A homologous set of 9,9-dialkyl-4,5-diazafluorene compounds were prepared by alkylation of 4,5-diazafluorene with the appropriate alkyl bromide and under basic conditions. The structures of these simple organic compounds were confirmed by spectroscopic techniques (FTIR, NMR, and FABMS). Their biological effects toward a panel of human carcinoma cells, including Hep3B hepatocellular carcinoma, MDAMB-231 breast carcinoma, and SKHep-1 hepatoma cells, were investigated; a structure,activity correlation was established with respect to the length of the alkyl chain and the fluorene ring structure. The relationship between the mean potency [log(1/IC50)] and alkyl chain length was systematically studied. The results show that compounds with butyl, hexyl, and octyl chains exhibit good growth inhibitory effects toward these three human carcinoma cell lines, and the 9,9-dihexyl-4,5-diazafluorene further exhibits antitumor activity in athymic nude mice Hep3B xenograft models. For the structurally related dialkylfluorenes that lack the diaza functionality, in,vitro cytotoxicity was not observed at clinically relevant concentrations. [source] | ||||||||||||||||