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Bernardo A. Mainou - One of the best experts on this subject based on the ideXlab platform.

  • Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors.
    Journal of virology, 2019
    Co-Authors: Roxana M Rodriguez Stewart, Jameson T.l. Berry, Angela K. Berger, Sung Bo Yoon, Jaime A Guberman, Nirav B. Patel, Gregory K. Tharp, Steven E. Bosinger, Aspen L Hirsch, Bernardo A. Mainou
    Abstract:

    Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule Inhibitors, we identified Topoisomerase Inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with Topoisomerase Inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with Topoisomerase Inhibitors more efficiently infect and kill triple-negative breast cancer cells.IMPORTANCE Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and Topoisomerase Inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.

  • Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors
    bioRxiv, 2019
    Co-Authors: Roxana M Rodriguez Stewart, Jameson T.l. Berry, Angela K. Berger, Sung Bo Yoon, Jaime A Guberman, Nirav B. Patel, Gregory K. Tharp, Steven E. Bosinger, Bernardo A. Mainou
    Abstract:

    Breast cancer is the second-leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and whether addition of small molecule Inhibitors enhances reovirus-induced cytotoxicity of breast cancer cells. Here, we generate reassortant reoviruses by forward genetics that infect and kill triple-negative breast cancer cells more efficiently than parental viruses. From a high-throughput screen of small molecule Inhibitors, we identified Topoisomerase Inhibitors as drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of cells with Topoisomerase Inhibitors activates the DNA damage response and infection with reovirus induces robust production of Type III, but not Type I, interferon. Together, data presented show that reassortant viruses generated by forward genetics in combination with Topoisomerase Inhibitors more efficiently infect and kill triple-negative breast cancer cells.

Roxana M Rodriguez Stewart - One of the best experts on this subject based on the ideXlab platform.

  • Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors.
    Journal of virology, 2019
    Co-Authors: Roxana M Rodriguez Stewart, Jameson T.l. Berry, Angela K. Berger, Sung Bo Yoon, Jaime A Guberman, Nirav B. Patel, Gregory K. Tharp, Steven E. Bosinger, Aspen L Hirsch, Bernardo A. Mainou
    Abstract:

    Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule Inhibitors, we identified Topoisomerase Inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with Topoisomerase Inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with Topoisomerase Inhibitors more efficiently infect and kill triple-negative breast cancer cells.IMPORTANCE Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and Topoisomerase Inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.

  • Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors
    bioRxiv, 2019
    Co-Authors: Roxana M Rodriguez Stewart, Jameson T.l. Berry, Angela K. Berger, Sung Bo Yoon, Jaime A Guberman, Nirav B. Patel, Gregory K. Tharp, Steven E. Bosinger, Bernardo A. Mainou
    Abstract:

    Breast cancer is the second-leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and whether addition of small molecule Inhibitors enhances reovirus-induced cytotoxicity of breast cancer cells. Here, we generate reassortant reoviruses by forward genetics that infect and kill triple-negative breast cancer cells more efficiently than parental viruses. From a high-throughput screen of small molecule Inhibitors, we identified Topoisomerase Inhibitors as drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of cells with Topoisomerase Inhibitors activates the DNA damage response and infection with reovirus induces robust production of Type III, but not Type I, interferon. Together, data presented show that reassortant viruses generated by forward genetics in combination with Topoisomerase Inhibitors more efficiently infect and kill triple-negative breast cancer cells.

Dietmar Steverding - One of the best experts on this subject based on the ideXlab platform.

  • In vitro antifungal activity of DNA Topoisomerase Inhibitors
    Medical Mycology, 2011
    Co-Authors: Dietmar Steverding, Penelope Evans, Leon Msika, Benjamin Riley, Jerome Wallington, Silke Schelenz
    Abstract:

    In this paper we report the results of the study of the in vitro effect of eight anticancer DNA Topoisomerase Inhibitors on the growth of Aspergillus fumigatus, A. niger, Candida glabrata and Cryptococcus neoformans. Only one compound, idarubicin, displayed promising antifungal activity against A. niger, C. glabrata and C. neoformans with MIC50 values varying between 3.6 and 14.2 μM (1.8–7.1 μg/ml). Three other compounds, aclarubicin, doxorubicin and mitoxantrone, showed some antifungal activity against C. glabrata and C. neoformans with MIC50 values in the mid micromolar range. The data of this study indicate that selected DNA Topoisomerase Inhibitors are a promising class of compounds for the development of new antifungal agents.

  • In vitro effect of DNA Topoisomerase Inhibitors on Candida albicans.
    Medical mycology, 2010
    Co-Authors: Shing C. Kwok, Silke Schelenz, Xia Wang, Dietmar Steverding
    Abstract:

    In this study we investigated the in vitro antifungal activity of 10 DNA Topoisomerase Inhibitors on the growth of Candida albicans. The EUCAST broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of the compounds for C. albicans. In addition, the effect of the Inhibitors on the growth mode of C. albicans was investigated by light microscopy imaging. Of the 10 DNA Topoisomerase Inhibitors tested, only the anti-cancer drug aclarubicin displayed antifungal activity with a determinable MIC value of 8.4 microg/ml (10.3 microM). Aclarubicin was also active against clinical isolates of C. albicans with MIC values ranging between 0.8 and 7.3 microg/ml (1-9 microM). Vitality assays showed that the action of aclarubicin was fungistatic. Four other DNA Topoisomerase Inhibitors, daunorubicin, doxorubicin, idarubicin and beta-lapachone, affected the morphology of C. albicans. The first three Inhibitors encouraged the fungus to grow predominantly in the yeast form, whereas beta-lapachone caused hyphal proliferation. The results of this study indicate that some DNA Topoisomerase Inhibitors effect the growth and morphology of C. albicans suggesting a possible role as antifungal agents in the treatment of C. albicans infections.

  • Anti-trypanosomal activities of DNA Topoisomerase Inhibitors
    Acta Tropica, 2005
    Co-Authors: Alexander Deterding, Fiona A. Dungey, Katy-anne Thompson, Dietmar Steverding
    Abstract:

    AbstractOnly four drugs are available for chemotherapy of human African sleeping sickness with undesirable toxic side effects. Thedevelopment of new anti-trypanosomal drugs is, therefore, urgently required. In this study, 15 DNA Topoisomerase Inhibitors,including approved anti-cancer drugs, were tested for in vitro activity against bloodstream forms ofTrypanosoma brucei andhumanleukaemiaHL-60cells.Allcompoundsexhibitedanti-trypanosomalactivity,withED 50 valuesrangingbetween3nMand30 M, and MIC values between 100nM and >100 M. The trypanocidal activities of the most effective DNA TopoisomeraseInhibitors, aclarubicin, doxorubicin and mitoxantrone, were comparable with those of commercial anti-trypanosomal drugs.These data support the use of DNA Topoisomerase Inhibitors as lead compounds for anti-trypanosomal drug development.© 2005 Elsevier B.V. All rights reserved. Keywords: Trypanosoma brucei ; Sleeping sickness; DNA Topoisomerase Inhibitors; Drug screening; Chemotherapy 1. IntroductionHuman African trypanosomiasis or sleeping sick-ness is a deadly disease that is caused by the protozoanparasite Trypanosoma brucei . The parasite is transmit-tedbyinfectedtsetsefliesandlivesextracelluarlyintheblood and tissue fluids of their mammalian host. Sleep-ing sickness has re-emerged in recent years, so that

  • Anti-trypanosomal activities of DNA Topoisomerase Inhibitors.
    Acta tropica, 2005
    Co-Authors: Alexander Deterding, Fiona A. Dungey, Katy-anne Thompson, Dietmar Steverding
    Abstract:

    Only four drugs are available for chemotherapy of human African sleeping sickness with undesirable toxic side effects. The development of new anti-trypanosomal drugs is, therefore, urgently required. In this study, 15 DNA Topoisomerase Inhibitors, including approved anti-cancer drugs, were tested for in vitro activity against bloodstream forms of Trypanosoma brucei and human leukaemia HL-60 cells. All compounds exhibited anti-trypanosomal activity, with ED50 values ranging between 3 nM and 30 microM, and MIC values between 100 nM and >100 microM. The trypanocidal activities of the most effective DNA Topoisomerase Inhibitors, aclarubicin, doxorubicin and mitoxantrone, were comparable with those of commercial anti-trypanosomal drugs. These data support the use of DNA Topoisomerase Inhibitors as lead compounds for anti-trypanosomal drug development.

Angela K. Berger - One of the best experts on this subject based on the ideXlab platform.

  • Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors.
    Journal of virology, 2019
    Co-Authors: Roxana M Rodriguez Stewart, Jameson T.l. Berry, Angela K. Berger, Sung Bo Yoon, Jaime A Guberman, Nirav B. Patel, Gregory K. Tharp, Steven E. Bosinger, Aspen L Hirsch, Bernardo A. Mainou
    Abstract:

    Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule Inhibitors, we identified Topoisomerase Inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with Topoisomerase Inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with Topoisomerase Inhibitors more efficiently infect and kill triple-negative breast cancer cells.IMPORTANCE Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and Topoisomerase Inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.

  • Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors
    bioRxiv, 2019
    Co-Authors: Roxana M Rodriguez Stewart, Jameson T.l. Berry, Angela K. Berger, Sung Bo Yoon, Jaime A Guberman, Nirav B. Patel, Gregory K. Tharp, Steven E. Bosinger, Bernardo A. Mainou
    Abstract:

    Breast cancer is the second-leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and whether addition of small molecule Inhibitors enhances reovirus-induced cytotoxicity of breast cancer cells. Here, we generate reassortant reoviruses by forward genetics that infect and kill triple-negative breast cancer cells more efficiently than parental viruses. From a high-throughput screen of small molecule Inhibitors, we identified Topoisomerase Inhibitors as drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of cells with Topoisomerase Inhibitors activates the DNA damage response and infection with reovirus induces robust production of Type III, but not Type I, interferon. Together, data presented show that reassortant viruses generated by forward genetics in combination with Topoisomerase Inhibitors more efficiently infect and kill triple-negative breast cancer cells.

Jameson T.l. Berry - One of the best experts on this subject based on the ideXlab platform.

  • Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors.
    Journal of virology, 2019
    Co-Authors: Roxana M Rodriguez Stewart, Jameson T.l. Berry, Angela K. Berger, Sung Bo Yoon, Jaime A Guberman, Nirav B. Patel, Gregory K. Tharp, Steven E. Bosinger, Aspen L Hirsch, Bernardo A. Mainou
    Abstract:

    Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule Inhibitors, we identified Topoisomerase Inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with Topoisomerase Inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with Topoisomerase Inhibitors more efficiently infect and kill triple-negative breast cancer cells.IMPORTANCE Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and Topoisomerase Inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.

  • Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors
    bioRxiv, 2019
    Co-Authors: Roxana M Rodriguez Stewart, Jameson T.l. Berry, Angela K. Berger, Sung Bo Yoon, Jaime A Guberman, Nirav B. Patel, Gregory K. Tharp, Steven E. Bosinger, Bernardo A. Mainou
    Abstract:

    Breast cancer is the second-leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and whether addition of small molecule Inhibitors enhances reovirus-induced cytotoxicity of breast cancer cells. Here, we generate reassortant reoviruses by forward genetics that infect and kill triple-negative breast cancer cells more efficiently than parental viruses. From a high-throughput screen of small molecule Inhibitors, we identified Topoisomerase Inhibitors as drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of cells with Topoisomerase Inhibitors activates the DNA damage response and infection with reovirus induces robust production of Type III, but not Type I, interferon. Together, data presented show that reassortant viruses generated by forward genetics in combination with Topoisomerase Inhibitors more efficiently infect and kill triple-negative breast cancer cells.