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  1. Article ; Online: MicroRNA regulation of cancer stem cells and therapeutic implications.

    DeSano, Jeffrey T / Xu, Liang

    The AAPS journal

    2009  Volume 11, Issue 4, Page(s) 682–692

    Abstract: MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNAs that function as important regulatory molecules by negatively regulating gene and protein expression via the RNA interference (RNAi) machinery. MiRNAs have been implicated to control a ... ...

    Abstract MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNAs that function as important regulatory molecules by negatively regulating gene and protein expression via the RNA interference (RNAi) machinery. MiRNAs have been implicated to control a variety of cellular, physiological, and developmental processes. Aberrant expressions of miRNAs are connected to human diseases such as cancer. Cancer stem cells are a small subpopulation of cells identified in a variety of tumors that are capable of self-renewal and differentiation. Dysregulation of stem cell self-renewal is a likely requirement for the initiation and formation of cancer. Furthermore, cancer stem cells are a very likely cause of resistance to current cancer treatments, as well as relapse in cancer patients. Understanding the biology and pathways involved with cancer stem cells offers great promise for developing better cancer therapies, and might one day even provide a cure for cancer. Emerging evidence demonstrates that miRNAs are involved in cancer stem cell dysregulation. Recent studies also suggest that miRNAs play a critical role in carcinogenesis and oncogenesis by regulating cell proliferation and apoptosis as oncogenes or tumor suppressors, respectively. Therefore, molecularly targeted miRNA therapy could be a powerful tool to correct the cancer stem cell dysregulation.
    MeSH term(s) Animals ; Gene Silencing ; Humans ; MicroRNAs/biosynthesis ; MicroRNAs/pharmacology ; MicroRNAs/therapeutic use ; Neoplasms/therapy ; Neoplastic Stem Cells/drug effects ; Signal Transduction/genetics ; Signal Transduction/physiology
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2009-10-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ISSN 1550-7416
    ISSN (online) 1550-7416
    DOI 10.1208/s12248-009-9147-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Celastrol potentiates radiotherapy by impairment of DNA damage processing in human prostate cancer.

    Dai, Yao / DeSano, Jeffrey T / Meng, Yang / Ji, Qing / Ljungman, Mats / Lawrence, Theodore S / Xu, Liang

    International journal of radiation oncology, biology, physics

    2009  Volume 74, Issue 4, Page(s) 1217–1225

    Abstract: Purpose: Celastrol is an active ingredient of traditional herbal medicine and has recently been identified as a potent natural proteasome inhibitor. In the present study, we evaluated the radiosensitizing potential of celastrol in the human prostate ... ...

    Abstract Purpose: Celastrol is an active ingredient of traditional herbal medicine and has recently been identified as a potent natural proteasome inhibitor. In the present study, we evaluated the radiosensitizing potential of celastrol in the human prostate cancer PC-3 model.
    Methods and materials: Clonogenic assays were performed to determine the radiosensitizing effect of celastrol. Apoptosis was examined by flow cytometry using Annexin V and propidium iodide staining and by a caspase-3 activation assay. DNA damage processing was examined by immunofluorescent staining and Western blot for phosphorylated H2AX (gammaH2AX). The PC-3 xenograft model in the athymic nude mouse was used for the determination of the in vivo efficacy of celastrol combined with radiotherapy. The tumor samples were also analyzed for apoptosis and angiogenesis.
    Results: Celastrol sensitized PC-3 cells to ionizing radiation (IR) in a dose- and schedule-dependent manner, in which pretreatment with celastrol for 1 h followed by IR achieved maximal radiosensitization. Celastrol significantly prolonged the presence of IR-induced gammaH2AX and increased IR-induced apoptosis. Celastrol, combined with fractionated radiation, significantly inhibited PC-3 tumor growth in vivo without obvious systemic toxicity. The combination treatment increased gammaH2AX levels and apoptosis, induced cleavage of poly(adenosine diphosphate-ribose)polymerase and Mcl-1, and reduced angiogenesis in vivo compared with either treatment alone.
    Conclusion: Celastrol sensitized PC-3 cells to radiation both in vitro and in vivo by impairing DNA damage processing and augmenting apoptosis. Celastrol might represent a promising new adjuvant regimen for the treatment of hormone-refractory prostate cancer.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; DNA Damage/drug effects ; Dose-Response Relationship, Radiation ; Enzyme Activation ; Female ; Flow Cytometry ; Histones/metabolism ; Humans ; Male ; Mice ; Mice, Nude ; Neovascularization, Pathologic/prevention & control ; Prostatic Neoplasms/blood supply ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/radiotherapy ; Radiation-Sensitizing Agents/therapeutic use ; Random Allocation ; Triterpenes/therapeutic use ; Xenograft Model Antitumor Assays/methods
    Chemical Substances H2AX protein, human ; Histones ; Radiation-Sensitizing Agents ; Triterpenes ; Caspase 3 (EC 3.4.22.-) ; celastrol (L8GG98663L)
    Language English
    Publishing date 2009-06-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 197614-x
    ISSN 1879-355X ; 0360-3016
    ISSN (online) 1879-355X
    ISSN 0360-3016
    DOI 10.1016/j.ijrobp.2009.03.057
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1218: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  3. Article ; Online: MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.

    Ji, Qing / Hao, Xinbao / Zhang, Min / Tang, Wenhua / Yang, Meng / Li, Ling / Xiang, Debing / Desano, Jeffrey T / Bommer, Guido T / Fan, Daiming / Fearon, Eric R / Lawrence, Theodore S / Xu, Liang

    PloS one

    2009  Volume 4, Issue 8, Page(s) e6816

    Abstract: Background: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family ... ...

    Abstract Background: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells.
    Methodology/principal findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+ MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.
    Conclusions/significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53-miR34, potentially via inhibiting pancreatic cancer stem cells.
    MeSH term(s) 3' Untranslated Regions ; AC133 Antigen ; Animals ; Antigens, CD/immunology ; Apoptosis ; Base Sequence ; Cell Cycle ; Cell Division ; DNA Primers ; Female ; Glycoproteins/immunology ; Humans ; Hyaluronan Receptors/immunology ; Mice ; Mice, Nude ; MicroRNAs/physiology ; Pancreatic Neoplasms/immunology ; Pancreatic Neoplasms/pathology ; Peptides/immunology ; Reverse Transcriptase Polymerase Chain Reaction
    Chemical Substances 3' Untranslated Regions ; AC133 Antigen ; Antigens, CD ; DNA Primers ; Glycoproteins ; Hyaluronan Receptors ; MicroRNAs ; PROM1 protein, human ; Peptides ; Prom1 protein, mouse
    Language English
    Publishing date 2009-08-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0006816
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Molecularly targeted radiosensitization of human prostate cancer by modulating inhibitor of apoptosis.

    Dai, Yao / Liu, Meilan / Tang, Wenhua / DeSano, Jeffrey / Burstein, Ezra / Davis, Mary / Pienta, Kenneth / Lawrence, Theodore / Xu, Liang

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2008  Volume 14, Issue 23, Page(s) 7701–7710

    Abstract: Purpose: The inhibitor of apoptosis proteins (IAP) are overexpressed in hormone-refractory prostate cancer, rendering the cancer cells resistant to radiation. This study aims to investigate the radiosensitizing effect of small-molecule IAP inhibitor ... ...

    Abstract Purpose: The inhibitor of apoptosis proteins (IAP) are overexpressed in hormone-refractory prostate cancer, rendering the cancer cells resistant to radiation. This study aims to investigate the radiosensitizing effect of small-molecule IAP inhibitor both in vitro and in vivo in androgen-independent prostate cancer and the possible mechanism of radiosensitization.
    Experimental design: Radiosensitization of SH-130 in human prostate cancer DU-145 cells was determined by clonogenic survival assay. Combination effect of SH-130 and ionizing radiation was evaluated by apoptosis assays. Pull-down and immunoprecipitation assays were employed to investigate the interaction between SH-130 and IAPs. DU-145 xenografts in nude mice were treated with SH-130, radiation, or combination, and tumor suppression effect was determined by caliper measurement or bioluminescence imaging. Nuclear factor-kappaB activation was detected by luciferase reporter assay and quantitative real-time PCR.
    Results: SH-130 potently enhanced radiation-induced caspase activation and apoptosis in DU-145 cells. Both X-linked IAP and cIAP-1 can be pulled down by SH-130 but not by inactive SH-123. Moreover, SH-130 interrupted interaction between X-linked IAP/cIAP-1 and Smac. In a nude mouse xenograft model, SH-130 potently sensitized the DU-145 tumors to X-ray radiation without increasing systemic toxicity. The combination therapy suppressed tumor growth more significantly than either treatment alone, with over 80% of complete tumor regression. Furthermore, SH-130 partially blocked tumor necrosis factor-alpha- and radiation-induced nuclear factor-kappaB activation in DU-145 cells.
    Conclusions: Our results show that small-molecule inhibitors of IAPs can overcome apoptosis resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Apoptosis/radiation effects ; Blotting, Western ; Cell Line, Tumor ; Combined Modality Therapy ; Female ; Humans ; Immunoprecipitation ; Inhibitor of Apoptosis Proteins/antagonists & inhibitors ; Inhibitor of Apoptosis Proteins/drug effects ; Inhibitor of Apoptosis Proteins/metabolism ; Male ; Mice ; NF-kappa B/drug effects ; NF-kappa B/radiation effects ; Oligopeptides/pharmacology ; Prostatic Neoplasms/therapy ; Radiation-Sensitizing Agents/pharmacology ; Radiotherapy ; Reverse Transcriptase Polymerase Chain Reaction ; Xenograft Model Antitumor Assays
    Chemical Substances Inhibitor of Apoptosis Proteins ; NF-kappa B ; Oligopeptides ; Radiation-Sensitizing Agents ; SH-130
    Language English
    Publishing date 2008-11-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-08-0188
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4223: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.

    Qing Ji / Xinbao Hao / Min Zhang / Wenhua Tang / Meng Yang / Ling Li / Debing Xiang / Jeffrey T Desano / Guido T Bommer / Daiming Fan / Eric R Fearon / Theodore S Lawrence / Liang Xu

    PLoS ONE, Vol 4, Iss 8, p e

    2009  Volume 6816

    Abstract: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was ... ...

    Abstract MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells.We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+ MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53-miR34, potentially via inhibiting pancreatic cancer stem ...
    Keywords Medicine ; R ; Science ; Q
    Subject code 610 ; 500
    Language English
    Publishing date 2009-08-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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