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Nancy E. Davidson - One of the best experts on this subject based on the ideXlab platform.

  • Paclitaxel induces programmed cell death in MDA-MB-468 human breast cancer cells.
    Clinical Cancer Research, 1996
    Co-Authors: Diane E. Mccloskey, Scott H. Kaufmann, Laura J. Prestigiacomo, Nancy E. Davidson
    Abstract:

    The ability of paclitaxel, one of the most active chemotherapeutic agents against breast cancer, to induce programmed cell death in hormone-independent MDA-MB-468 human breast cancer cells was assessed. Treatment of MDA-MB-468 cells led to growth inhibition, high-molecular-weight and oligonucleosomal DNA fragmentation, and apoptosis-associated morphological changes after either 3- or 24-h exposure to paclitaxel concentrations >/=10 nM. Additionally, cleavage products of poly(ADP-ribose) polymerase and lamin B1, two proteins that are cleaved early in the execution phase of programmed cell death, were detected. Quantitative studies indicated that exposure to paclitaxel for 24 h resulted in more DNA fragmentation than did 3-h exposure. Rapid induction of the early-response gene c-jun but not c-myc was associated with paclitaxel treatment. The ability of paclitaxel to induce high-molecular-weight DNA fragmentation and apoptosis-associated morphological changes in three other breast cancer cell lines was also established. These data suggest that paclitaxel, an agent known to stabilize microtubules and prevent cell division but not to act directly on DNA, induces programmed cell death in breast cancer cells.

  • Epidermal Growth Factor-mediated Apoptosis of MDA-MB-468 Human Breast Cancer Cells
    Cancer Research, 1994
    Co-Authors: Deborah K. Armstrong, Scott H. Kaufmann, Yvonne L. Ottaviano, Yuzo Furuya, Julie A. Buckley, John T. Isaacs, Nancy E. Davidson
    Abstract:

    Abstract MDA-MB-468 human breast cancer cells lack estrogen receptors, over-express epidermal growth factor (EGF) receptors, and are growth inhibited by EGF. We show that treatment of MDA-MB-468 cells with EGF leads to inhibition of cell proliferation, fragmentation of DNA into nucleosomal oligomers, and the development of apoptotic morphology. This treatment is associated with increased expression of c- myc , c- fos, jun family members, and transforming growth factor β 1 mRNA and with partial proteolytic cleavage of poly(ADP-ribose) polymerase and lamin B. The observation that EGF can mediate apoptosis in EGF receptor-over-expressing cells has important implications for clinical efforts directed at the EGF receptor.

  • Programmed cell death in an estrogen-independent human breast cancer cell line, MDA-MB-468.
    Cancer Research, 1992
    Co-Authors: Deborah K. Armstrong, Yvonne L. Ottaviano, John T. Isaacs, Nancy E. Davidson
    Abstract:

    Abstract Previous studies have demonstrated that estrogen-responsive human breast cancer cells can be induced to undergo an energy-dependent, genetically programmed series of biochemical changes that result in the active suicide of the cells following estrogen ablation. In contrast, estrogen-independent human breast cancer cells do not activate this programmed cell death pathway following estrogen ablation. This could be due either to the absence of the cellular machinery required for programmed cell death or simply to the inability of estrogen ablation to activate this machinery. To discriminate between these two possibilities, the MDA-MB-468 estrogen-independent human mammary adenocarcinoma cell line was used as a model system to study the mechanism of cell death following cytotoxic drug treatment. Exposure of these cells to the fluorinated pyrimidines, 5-fluoro-2′-deoxyuridine or trifluorothymidine, resulted in growth inhibition and loss of proliferative capacity within 24 h. These changes occurred while cell membrane integrity was intact as measured by either cellular morphology or trypan blue exclusion. After 48 h of drug treatment, loss of cell membrane integrity was followed by cell lysis and a rapid decline in cell number. The addition of 16 µm thymidine prior to drug treatment prevented cell death, but thymidine did not rescue these cells once drug treatment was initiated. Analysis of DNA revealed the characteristic fragmentation into nucleosomal oligomers that is a hallmark of programmed cell death. Associated with this death pathway was a 15-fold induction of transforming growth factor β1 gene expression that has been previously observed in a variety of cellular systems undergoing programmed cell death. These results indicate that MDA-MB-468 estrogen-independent human mammary carcinoma cells retain the ability to undergo programmed cell death after treatment with cytotoxic drugs that induce a “thymineless” state.

Gerry A. Potter - One of the best experts on this subject based on the ideXlab platform.

  • Anticancer effects of the flavonoid diosmetin on cell cycle progression and proliferation of MDA-MB 468 breast cancer cells due to CYP1 activation
    Oncology Reports, 2009
    Co-Authors: Vasilis P. Androutsopoulos, Sachin Mahale, Randolph R.j. Arroo, Gerry A. Potter
    Abstract:

    : Flavonoids constitute a large class of polyphenolic compounds with cancer preventative properties. We have examined the ability of the natural flavone diosmetin to inhibit proliferation of breast adenocarcinoma MDA-MB 468 and normal breast MCF-10A cells and found that this compound is selective for the cancer cells with slight toxicity in the normal breast cells. Diosmetin was metabolised to the structurally similar flavone luteolin in MDA-MB 468 cells, whereas no metabolism was seen in MCF-10A cells. Diosmetin caused G1 arrest at 10 microM in MDA-MB 468 cells after 48-h treatment whereas this effect was not observed in MCF-10A cells. We suggest that diosmetin exerts cytostatic effects in MDA-MB 468 cells, due to CYP1A1 and CYP1B1 catalyzed conversion to the flavone luteolin.

  • Antiproliferative and cytostatic effects of the natural product eupatorin on MDA-MB-468 human breast cancer cells due to CYP1-mediated metabolism
    Breast Cancer Research, 2008
    Co-Authors: Vasilis Androutsopoulos, Randolph R.j. Arroo, John F Hall, Somchaiya Surichan, Gerry A. Potter
    Abstract:

    Introduction The natural product eupatorin has been reported to have antiproliferative activity in tumour cell lines, but the exact mechanism is unclear. The cytochromes P450 CYP1B1, CYP1A1, and CYP1A2 have been shown to participate in the activation of various xenobiotics, compounds derived from the diet as well as chemotherapeutic drugs. CYP1B1 and CYP1A1 have also been proposed as targets for cancer chemotherapy for their differential and selective overexpression in tumour cells. In this study, we aimed to identify a possible mechanism of action for the antiproliferative effect of eupatorin, which can be attributed to CYP1 family-mediated metabolism. Methods The study focuses on the antiproliferative action of eupatorin on the human breast carcinoma cell line MDA-MB-468 and on a cell line derived from normal mammary tissue, MCF-10A. The cytotoxicity of the flavone, its effect on the cell cycle of the abovementioned cell lines, and its metabolism by CYP1 family enzymes were examined. Results Eupatorin showed a dose-dependent inhibitory effect of cell growth on MDA-MB-468 cells with a submicromolar median inhibition concentration (IC_50) whereas the IC_50 of this compound in MCF-10A cells was considerably higher. The antiproliferative effect, as measured by EROD (ethoxyresorufin- O -deethylase) assay and Western immunoblotting, was attributed mainly to CYP1A1 expression in MDA-MB-468 cells but not in MCF-10A cells. Moreover, CYP1 family enzymes were shown to metabolise eupatorin in vitro to the flavone cirsiliol and two other unidentified metabolites. Metabolism of eupatorin was also detected in MDA-MB-468 cell cultures, whereas metabolism by MCF-10A cells was negligible. Eupatorin was further shown to arrest the cell cycle of the CYP1-expressing cell line MDA-MB-468 in G_2/M phase, whereas no effect was observed in MCF-10A cells, which do not express CYP1 enzymes. The effect of eupatorin on the MDA-MB-468 cell cycle could be reversed by co-application of the CYP1 inhibitor acacetin. Conclusion The flavone eupatorin is selectively activated in breast cancer cells, but not in normal breast cells, due to CYP1 family metabolism. This provides a basis for selectivity which is desired against breast tumour cells. In this sense, eupatorin is shown by this study to be a very promising chemopreventative candidate that should be examined further in an in vivo study.

  • Antiproliferative and cytostatic effects of the natural product eupatorin on MDA-MB-468 human breast cancer cells due to CYP1-mediated metabolism
    Breast Cancer Research, 2008
    Co-Authors: Vasilis P. Androutsopoulos, Randolph R.j. Arroo, John F Hall, Somchaiya Surichan, Gerry A. Potter
    Abstract:

    The natural product eupatorin has been reported to have antiproliferative activity in tumour cell lines, but the exact mechanism is unclear. The cytochromes P450 CYP1B1, CYP1A1, and CYP1A2 have been shown to participate in the activation of various xenobiotics, compounds derived from the diet as well as chemotherapeutic drugs. CYP1B1 and CYP1A1 have also been proposed as targets for cancer chemotherapy for their differential and selective overexpression in tumour cells. In this study, we aimed to identify a possible mechanism of action for the antiproliferative effect of eupatorin, which can be attributed to CYP1 family-mediated metabolism. The study focuses on the antiproliferative action of eupatorin on the human breast carcinoma cell line MDA-MB-468 and on a cell line derived from normal mammary tissue, MCF-10A. The cytotoxicity of the flavone, its effect on the cell cycle of the abovementioned cell lines, and its metabolism by CYP1 family enzymes were examined. Eupatorin showed a dose-dependent inhibitory effect of cell growth on MDA-MB-468 cells with a submicromolar median inhibition concentration (IC50) whereas the IC50 of this compound in MCF-10A cells was considerably higher. The antiproliferative effect, as measured by EROD (ethoxyresorufin-O-deethylase) assay and Western immunoblotting, was attributed mainly to CYP1A1 expression in MDA-MB-468 cells but not in MCF-10A cells. Moreover, CYP1 family enzymes were shown to metabolise eupatorin in vitro to the flavone cirsiliol and two other unidentified metabolites. Metabolism of eupatorin was also detected in MDA-MB-468 cell cultures, whereas metabolism by MCF-10A cells was negligible. Eupatorin was further shown to arrest the cell cycle of the CYP1-expressing cell line MDA-MB-468 in G2/M phase, whereas no effect was observed in MCF-10A cells, which do not express CYP1 enzymes. The effect of eupatorin on the MDA-MB-468 cell cycle could be reversed by co-application of the CYP1 inhibitor acacetin. The flavone eupatorin is selectively activated in breast cancer cells, but not in normal breast cells, due to CYP1 family metabolism. This provides a basis for selectivity which is desired against breast tumour cells. In this sense, eupatorin is shown by this study to be a very promising chemopreventative candidate that should be examined further in an in vivo study.

Frank Entschladen - One of the best experts on this subject based on the ideXlab platform.

  • Neutrophil granulocytes promote the migratory activity of MDA-MB-468 human breast carcinoma cells via ICAM-1
    Experimental Cell Research, 2009
    Co-Authors: Carina Strell, Kerstin Lang, Bernd Niggemann, Kurt S. Zaenker, Frank Entschladen
    Abstract:

    Abstract Tumor infiltrating neutrophil granulocytes do not only exhibit tumor eliminating functions but also promote tumor progression. We have recently shown that neutrophil granulocytes can serve as linking cells for the adhesion of MDA-MB-468 breast carcinoma cells to pulmonary endothelium. Neutrophil granulocytes but not MDA-MB-468 cells express β 2 -integrins, the ligands of the intercellular adhesion molecule (ICAM)-1, whereas ICAM-1 is strongly expressed on MDA-MB-468 cells. Consequently, the herein presented study was performed to investigate if this interaction has also an influence on the migratory activity of the tumor cells and whether ICAM-1 signaling plays a role in this process, too. We found that the continuous release of interleukin-8 (IL-8) and GRO-α by MDA-MB-468 cells increases the migratory activity of neutrophil granulocytes and attracts these cells towards the tumor cells which enables direct cell–cell interactions. These interactions in turn increase the migratory activity of the tumor cells in an ICAM-1 clustering-dependent mechanism since transfection of the tumor cells with specific siRNA against ICAM-1 abolished the effect. Moreover, ICAM-1 cross-linking on tumor cells induces the phosphorylation of focal adhesion components such as focal adhesion kinase and paxillin via src kinase as well as the activation of the p38 MAPK pathway via Rho kinase in a time-dependent manner. Our results provide evidence that ICAM-1 is coupled to intracellular signaling pathways involved in tumor cell migration. Thus, neutrophil granulocytes can act as modulators of the metastatic capability of tumor cells by ligation of ICAM-1.

  • Surface molecules regulating rolling and adhesion to endothelium of neutrophil granulocytes and MDA-MB-468 breast carcinoma cells and their interaction
    Cellular and Molecular Life Sciences, 2007
    Co-Authors: Carina Strell, Kerstin Lang, Bernd Niggemann, Kurt S. Zaenker, Frank Entschladen
    Abstract:

    The extravasation of leukocytes and tumor cells is a multi-step process with the involvement of various adhesion molecules depending on the three steps rolling, adhesion, and diapedesis. We have developed an in vitro model, by which we investigated the rolling and adhesion of neutrophil granulocytes and MDA-MB-468 human breast carcinoma cells to lung endothelial cells under physiological flow-conditions. We found that norepinephrine had an inhibitory function on the fMLP-promoted adhesion of neutrophil granulocytes due to a down-regulation of β2-integrin. Furthermore, neutrophil granulocytes serve as linking cells for the interaction of the MDA-MB-468 cells with the endothelium, which are both β2-integrin negative, but express the β2-integrin ligand ICAM-1. In addition, we show here that N-cadherin is up-regulated on the endothelial cells and on neutrophil granulocytes in response to fMLP. This up-regulation resulted in a significant increase of adherent MDA-MB-468 cells, which are also N-cadherin positive.

  • Phosphatidylinositol 3-Kinase in the G Protein-Coupled Receptor-Induced Chemokinesis and Chemotaxis of MDA-MB-468 Breast Carcinoma Cells: A Comparison with Leukocytes
    Molecular Cancer Research, 2006
    Co-Authors: Philipp Bastian, Kerstin Lang, Bernd Niggemann, Kurt S. Zaenker, Birte Posch, Hanns Hatt, Frank Entschladen
    Abstract:

    The polarization of tumor cells and leukocytes into a front end and a rear end is a crucial prerequisite for their autonomous, directed movement. Phosphatidylinositol 3-kinase (PI3K) is assumed to play an important role in this polarization process, whereas the results obtained with different cell types and different migration assays widely vary. Thus, we conducted a comparative study on the role of the PI3K in the locomotor activity and directionality of the migration of tumor cells on the example of MDA-MB-468 breast carcinoma cells in comparison with CTLs and neutrophil granulocytes. We used our well-established, collagen-based, three-dimensional migration assay for the investigation of the chemokinesis and chemotaxis of these cells. Our results show that the role of the PI3K in the regulation of migratory activity is distinct between the investigated cell types: the migration of CTLs and MDA-MB-468 cells was impaired by the inhibition of the PI3K with wortmannin, whereas neutrophil granulocytes were only slightly affected. However, neither cell type was impaired in the ability to respond chemotactically to gradients of ligands to G protein-coupled receptors. Thus, the PI3K contributes to the regulation of migratory activity but not to the directionality of migration of MDA-MB-468 breast carcinoma cells. As a further conclusion with regard to cancer treatment, the PI3K is not a suitable target for the inhibition of metastasis formation, because the migration of leukocytes is also affected, which leads to a dysfunction of the immune defense. (Mol Cancer Res 2006;4(6):411–21)

Deborah K. Armstrong - One of the best experts on this subject based on the ideXlab platform.

  • Epidermal Growth Factor-mediated Apoptosis of MDA-MB-468 Human Breast Cancer Cells
    Cancer Research, 1994
    Co-Authors: Deborah K. Armstrong, Scott H. Kaufmann, Yvonne L. Ottaviano, Yuzo Furuya, Julie A. Buckley, John T. Isaacs, Nancy E. Davidson
    Abstract:

    Abstract MDA-MB-468 human breast cancer cells lack estrogen receptors, over-express epidermal growth factor (EGF) receptors, and are growth inhibited by EGF. We show that treatment of MDA-MB-468 cells with EGF leads to inhibition of cell proliferation, fragmentation of DNA into nucleosomal oligomers, and the development of apoptotic morphology. This treatment is associated with increased expression of c- myc , c- fos, jun family members, and transforming growth factor β 1 mRNA and with partial proteolytic cleavage of poly(ADP-ribose) polymerase and lamin B. The observation that EGF can mediate apoptosis in EGF receptor-over-expressing cells has important implications for clinical efforts directed at the EGF receptor.

  • Programmed cell death in an estrogen-independent human breast cancer cell line, MDA-MB-468.
    Cancer Research, 1992
    Co-Authors: Deborah K. Armstrong, Yvonne L. Ottaviano, John T. Isaacs, Nancy E. Davidson
    Abstract:

    Abstract Previous studies have demonstrated that estrogen-responsive human breast cancer cells can be induced to undergo an energy-dependent, genetically programmed series of biochemical changes that result in the active suicide of the cells following estrogen ablation. In contrast, estrogen-independent human breast cancer cells do not activate this programmed cell death pathway following estrogen ablation. This could be due either to the absence of the cellular machinery required for programmed cell death or simply to the inability of estrogen ablation to activate this machinery. To discriminate between these two possibilities, the MDA-MB-468 estrogen-independent human mammary adenocarcinoma cell line was used as a model system to study the mechanism of cell death following cytotoxic drug treatment. Exposure of these cells to the fluorinated pyrimidines, 5-fluoro-2′-deoxyuridine or trifluorothymidine, resulted in growth inhibition and loss of proliferative capacity within 24 h. These changes occurred while cell membrane integrity was intact as measured by either cellular morphology or trypan blue exclusion. After 48 h of drug treatment, loss of cell membrane integrity was followed by cell lysis and a rapid decline in cell number. The addition of 16 µm thymidine prior to drug treatment prevented cell death, but thymidine did not rescue these cells once drug treatment was initiated. Analysis of DNA revealed the characteristic fragmentation into nucleosomal oligomers that is a hallmark of programmed cell death. Associated with this death pathway was a 15-fold induction of transforming growth factor β1 gene expression that has been previously observed in a variety of cellular systems undergoing programmed cell death. These results indicate that MDA-MB-468 estrogen-independent human mammary carcinoma cells retain the ability to undergo programmed cell death after treatment with cytotoxic drugs that induce a “thymineless” state.

Gabor Halmos - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of growth of MDA-MB-468 estrogen-independent human breast carcinoma by bombesin/gastrin-releasing peptide antagonists RC-3095 and RC-3940-II.
    Cancer, 2000
    Co-Authors: Zsuzsanna Kahán, M.d.h.c. Andrew V. Schally, José M. Arencibia, Kate Groot, Gabor Halmos
    Abstract:

    BACKGROUND The growth of breast carcinoma is promoted by autocrine growth factors such as the bombesin (BN)-like peptides and epidermal growth factor (EGF). The stimulatory action of BN-like peptides can be blocked by the use of BN/gastrin-releasing peptide (GRP) antagonists. METHODS The authors investigated the effects of synthetic BN/GRP antagonists RC-3095 and RC-3940-II on tumor growth and the expression of mRNA for EGF receptors and three BN receptor subtypes in MDA-MB-468 human breast carcinoma. Athymic nude mice with xenografts of MDA-MB-468 human breast carcinoma were injected subcutaneously for 6 weeks with RC-3940-II at doses of 20 or 40 μg/day. In another study, the effects of RC-3940-II and RC-3095 were compared. RESULTS RC-3940-II caused a significant and dose-dependent growth inhibition of MDA-MB-468 tumors in nude mice; therapy with either dose of RC-3940-II significantly (P 50% of all tumors. One of 3 tumors treated with 20 μg of RC-3940-II and 3 of 5 tumors treated with 40 μg were found to have regressed completely by the end of the study. When RC-3940-II and RC-3095 were compared at the dose of 20 μg/day, both powerfully suppressed growth of MDA-MB-468 tumors, with RC-3940-II causing a complete regression of 2 tumors and RC-3095 a complete regression of 1 tumor. Receptor analyses of untreated MDA-MB-468 tumors revealed an overexpression of EGF receptors and two classes of binding sites for BN/GRP. mRNAs for receptors of GRP, neuromedin B, and BN receptor subtype-3 were detected by reverse transcriptase-polymerase chain reaction. CONCLUSIONS A virtual arrest of growth or regression of MDA-MB-468 human breast carcinoma after therapy with RC-3940-II and RC-3095 indicates that these BN/GRP antagonists could provide a new treatment modality for breast tumors expressing BN and EGF receptors. Cancer 2000;88:1384–92. © 2000 American Cancer Society.

  • Antagonists of growth hormone-releasing hormone arrest the growth of MDA-MB-468 estrogen-independent human breast cancers in nude mice.
    Breast Cancer Research and Treatment, 2000
    Co-Authors: Zsuzsanna Kahán, Jozsef L. Varga, Andrew V. Schally, Zoltan Rekasi, Patricia Armatis, Ioulia Chatzistamou, Tamas Czompoly, Gabor Halmos
    Abstract:

    Since antagonists of growth hormone-releasing hormone (GH-RH) inhibit proliferation of various tumors, in this study we investigated the effects of GH-RH antagonists MZ-5-156 or JV-1-36 on growth of estrogen-independent MDA-MB-468 human breast cancers xenografted into nude mice. Both GH-RH antagonists administered at a dose of 20 μg/day induced regression of some and growth-arrest of other tumors, while control tumors continued to grow. After 5 weeks of therapy with MZ-5-156 or JV-1-36, final volume and weight of MDA-MB-468 tumors were significantly decreased (all p values