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      1. Author :
        Stan, Silvia D; Hahm, Eun-Ryeong; Warin, Renaud; Singh, Shivendra V
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        68
      8. Issue :
        18
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Bioware; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Ergosterol; Female; Forkhead Transcription Factors; Humans; MDA-MB-231-D3H1 cells; Membrane Proteins; Mice; Mice, Nude; Proto-Oncogene Proteins; RNA, Small Interfering; Transfection; Withanolides; Xenograft Model Antitumor Assays
      12. Abstract :
        Withaferin A (WA) is derived from the medicinal plant Withania somnifera, which has been safely used for centuries in Indian Ayurvedic medicine for treatment of different ailments. We now show, for the first time, that WA exhibits significant activity against human breast cancer cells in culture and in vivo. The WA treatment decreased viability of MCF-7 (estrogen-responsive) and MDA-MB-231 (estrogen-independent) human breast cancer cells in a concentration-dependent manner. The WA-mediated suppression of breast cancer cell viability correlated with apoptosis induction characterized by DNA condensation, cytoplasmic histone-associated DNA fragmentation, and cleavage of poly-(ADP-ribose)-polymerase. On the other hand, a spontaneously immortalized normal mammary epithelial cell line (MCF-10A) was relatively more resistant to WA-induced apoptosis compared with breast cancer cells. The WA-mediated apoptosis was accompanied by induction of Bim-s and Bim-L in MCF-7 cells and induction of Bim-s and Bim-EL isoforms in MDA-MB-231 cells. The cytoplasmic histone-associated DNA fragmentation resulting from WA exposure was significantly attenuated by knockdown of protein levels of Bim and its transcriptional regulator FOXO3a in both cell lines. Moreover, FOXO3a knockdown conferred marked protection against WA-mediated induction of Bim-s expression. The growth of MDA-MB-231 cells implanted in female nude mice was significantly retarded by 5 weekly i.p. injections of 4 mg WA/kg body weight. The tumors from WA-treated mice exhibited reduced cell proliferation and increased apoptosis compared with tumors from control mice. These results point toward an important role of FOXO3a and Bim in regulation of WA-mediated apoptosis in human breast cancer cells.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18794155
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8990
      1. Author :
        Huang, Yujie; Song, Nan; Ding, Yanping; Yuan, Shaopeng; Li, Xuhui; Cai, Hongchen; Shi, Hubing; Luo, Yongzhang
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        69
      8. Issue :
        19
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Angiopoietin-2; Animals; Bioware; Breast Neoplasms; Capillary Permeability; Female; Gene Expression; Humans; Lung; Lung Neoplasms; Matrix Metalloproteinase 10; Matrix Metalloproteinase 3; MDA-MB-231-D3H1 cells; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Nude; RNA Interference; Up-Regulation
      12. Abstract :
        Before metastasis, certain organs have already been influenced by primary tumors. However, the exact alterations and regulatory mechanisms of the premetastatic organs remain poorly understood. Here, we report that, in the premetastatic stage, angiopoietin 2 (Angpt2), matrix metalloproteinase (MMP) 3, and MMP10 are up-regulated in the lung by primary B16/F10 tumor, which leads to the increased permeability of pulmonary vasculatures and extravasation of circulating tumor cells. Subsequent studies show that Angpt2, MMP3, and MMP10 have a synergistic effect on disrupting vascular integrity in both in vitro and in vivo models. Lentivirus-based in vivo RNA interference of Angpt2, MMP3, and MMP10 attenuates the pulmonary vascular permeability and suppresses the infiltration of myeloid cells in the premetastatic lung. Moreover, knocking down these factors significantly inhibits the spontaneous lung metastasis in the model by orthotopic implantation of MDA-MB-231-Luc-D3H1 cells in nude mice. Further investigations reveal that the malignancy of tumor cells is positively correlated with their capabilities to induce the expression of Angpt2, MMP3, and MMP10. Luciferase reporter assay and chromatin immunoprecipitation assay also suggest that transforming growth factor-beta1 and tumor necrosis factor-alpha signaling are involved in the regulation of these premetastatic factors. Our study shows that pulmonary vascular destabilization in the premetastatic phase promotes the extravasation of tumor cells and facilitates lung metastasis, which may provide potential targets for clinical prevention of metastasis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19773447
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8989
      1. Author :
        Marttila-Ichihara, Fumiko; Auvinen, Kaisa; Elima, Kati; Jalkanen, Sirpa; Salmi, Marko
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        69
      8. Issue :
        19
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Amine Oxidase (Copper-Containing); Animals; Antigens, CD11b; B16-F10-luc-G5 cells; Bioware; Cell Adhesion Molecules; Cell Growth Processes; Female; Lymphoma; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells; Neovascularization, Pathologic; Oxidoreductases; Receptors, Chemokine
      12. Abstract :
        Cancer growth is regulated by several nonmalignant cell types, such as leukocytes and endothelial cells, which reside in the stroma of the tumor. Vascular adhesion protein-1 (VAP-1) is an amine oxidase enzyme that is expressed on the surface of endothelial cells. It supports leukocyte traffic into inflamed tissues, but nothing is known about its possible role in cancer biology in vivo. Here, we report that B16 melanoma and EL-4 lymphoma remain smaller in VAP-1-deficient mice than in wild-type controls. We found an unexpected defect in tumor angiogenesis in the absence of VAP-1. VAP-1 also selectively enhanced the recruitment of Gr-1+CD11b+ myeloid cells into the tumors. Generation of mice expressing enzymatically inactive VAP-1 showed that the oxidase activity of VAP-1 was necessary to support neoangiogenesis, myeloid cell recruitment, and tumor growth in vivo. These data describe VAP-1 as the first adhesion molecule known to be involved in the recruitment of Gr-1+CD11b+ myeloid cells into tumors. They also suggest that VAP-1 is a potential new tool for immunotherapy of tumors that could be exploited to reduce tumor burden by controlling the traffic of Gr-1+CD11b+ myeloid cells.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19789345
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8997
      1. Author :
        Francis, K P; Yu, J; Bellinger-Kawahara, C; Joh, D; Hawkinson, M J; Xiao, G; Purchio, T F; Caparon, M G; Lipsitch, M; Contag, P R
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2001
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        69
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Amoxicillin; Animals; Bioware; DNA Transposable Elements; Female; Luminescent Measurements; Lung; Mice; Mice, Inbred BALB C; Nasopharynx; Operon; Promoter Regions, Genetic; pXen-5; Streptococcus pneumoniae; Transformation, Bacterial, Xen10, Xen7
      12. Abstract :
        Animal studies with Streptococcus pneumoniae have provided valuable models for drug development. In order to monitor long-term pneumococcal infections noninvasively in living mice, a novel gram-positive lux transposon cassette, Tn4001 luxABCDE Km(r), that allows random integration of lux genes onto the bacterial chromosome was constructed. The cassette was designed so that the luxABCDE and kanamycin resistance genes were linked to form a single promoterless operon. Bioluminescence and kanamycin resistance only occur in a bacterial cell if this operon has transposed downstream of a promoter on the bacterium's chromosome. S. pneumoniae D39 was transformed with plasmid pAUL-A Tn4001 luxABCDE Km(r), and a number of highly bioluminescent colonies were recovered. Genomic DNA from the brightest D39 strain was used to transform a number of clinical S. pneumoniae isolates, and several of these strains were tested in animal models, including a pneumococcal lung infection model. Strong bioluminescent signals were seen in the lungs of the animals containing these pneumococci, allowing the course and antibiotic treatment of the infections to be readily monitored in real time in the living animals. Recovery of the bacteria from the animals showed that the bioluminescent signal corresponded to the number of CFU and that the lux construct was highly stable even after several days in vivo. We believe that this lux transposon will greatly expand the ability to evaluate drug efficacy against gram-positive bacteria in living animals using bioluminescence.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/11292758
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9027
      1. Author :
        Laurie E. Littlepage; Mark D. Sternlicht; Nathalie Rougier; Joanna Phillips; Eugenio Gallo; Ying Yu; Kurt Williams; Audrey Brenot; Jeffrey I. Gordon; Zena Werb
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer Research
      6. Products :
      7. Volume :
        70
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        matrix metalloproteinase; neuroendocrine; prostate cancer; metatasis
      12. Abstract :
        Prostate cancer is the leading form of cancer in men. Prostate tumors often contain neuroendocrine differentiation, which correlates with androgen-independent progression and poor prognosis. Matrix metalloproteinases (MMP), a family of enzymes that remodel the microenvironment, are associated with tumorigenesis and metastasis. To evaluate MMPs during metastatic prostatic neuroendocrine cancer development, we used transgenic mice expressing SV40 large T antigen in their prostatic neuroendocrine cells, under the control of transcriptional regulatory elements from the mouse cryptdin-2 gene (CR2-TAg). These mice have a stereotypical pattern of tumorigenesis and metastasis. MMP-2, MMP-7, and MMP-9 activities increased concurrently with the transition to invasive metastatic carcinoma, but they were expressed in different prostatic cell types: stromal, luminal epithelium, and macrophages, respectively. CR2-TAg mice treated with AG3340/Prinomastat, an MMP inhibitor that blocks activity of MMP-2, MMP-9, MMP-13, and MMP-14, had reduced tumor burden. CR2-TAg animals were crossed to mice homozygous for null alleles of MMP-2, MMP-7, or MMP-9 genes. At 24 weeks CR2-TAg; MMP-2-/- mice showed reduced tumor burden, prolonged survival, decreased lung metastasis, and decreased blood vessel density, whereas deficiencies in MMP-7 or MMP-9 did not influence tumor growth or survival. Mice deficient for MMP-7 had reduced endothelial area coverage and decreased vessel size, and mice lacking MMP-9 had increased numbers of invasive foci and increased perivascular invasion, as well as decreased tumor blood vessel size. Together, these results suggest distinct contributions by MMPs to the progression of aggressive prostate tumor and to helping tumors cleverly find alternative routes to malignant progression.
      13. URL :
        http://cancerres.aacrjournals.org/content/70/6/2224.abstract
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4490
      1. Author :
        Holland, Sacha J; Pan, Alison; Franci, Christian; Hu, Yuanming; Chang, Betty; Li, Weiqun; Duan, Matt; Torneros, Allan; Yu, Jiaxin; Heckrodt, Thilo J; Zhang, Jing; Ding, Pingyu; Apatira, Ayodele; Chua, Joanne; Brandt, Ralf; Pine, Polly; Goff, Dane; Singh, Rajinder; Payan, Donald G; Hitoshi, Yasumichi
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        70
      8. Issue :
        4
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents; Benzocycloheptenes; Bioware; Breast Neoplasms; Carcinoma; Female; Hela Cells; Humans; K562 Cells; MDA-MB-231-D3H2LN cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Oncogene Proteins; Protein kinase inhibitors; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Survival Analysis; Triazoles; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
      12. Abstract :
        Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, >80 days compared with 52 days; P < 0.05) mouse models of breast cancer metastasis. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20145120
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8949
      1. Author :
        Nguyen, V. H.; Kim, H. S.; Ha, J. M.; Hong, Y.; Choy, H. E.; Min, J. J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer Res
      6. Products :
      7. Volume :
        70
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, Blotting, Western, Xen26, Cell Line, Tumor, Diagnostic Imaging/methods, Gene Therapy/*methods, Genetic Engineering/*methods, Genetic Vectors/*therapeutic use, Humans, Male, Mice, Mice, Inbred BALB C, Neoplasms/*therapy, Perforin/*genetics/therapeutic use, Promoter Regions, Genetic, Salmonella typhimurium/*genetics, bcl-Associated Death Protein/genetics IVIS, Xenogen
      12. Abstract :
        Tumor-targeting bacteria have been studied in terms of their ability to visualize the infection pathway (through imaging probes) or to carry therapeutic molecules to tumors. To integrate these monitoring and therapeutic functions, we engineered attenuated Salmonella typhimurium defective in guanosine 5'-diphosphate-3'-diphosphate synthesis to carry cytotoxic proteins (cytolysin A) and express reporter genes. We successfully visualized the therapeutic process with these engineered bacteria in mice and found that they often mediated complete tumor (CT-26) eradication on cytotoxic gene induction. Furthermore, treatment with the engineered bacteria markedly suppressed metastatic tumor growth.
      13. URL :
        http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20028866
      14. Call Number :
        141643
      15. Serial :
        6246
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